Human glucagon-like-peptide-1 mimics and their use in the treatment of diabetes and related conditions

ABSTRACT

The present invention provides novel human glucagon-like peptide-1 (GLP-1) peptide mimics that mimic the biological activity of the native GLP-1 peptide and thus are useful for the treatment or prevention of diseases or disorders associated with GLP activity. Further, the present invention provides novel, chemically modified peptides that not only stimulate insulin secretion in type II diabetics, but also produce other beneficial insulinotropic responses. These synthetic peptide GLP-1 mimics exhibit increased stability to proteolytic cleavage making them ideal therapeutic candidates for oral or parenteral administration.

[0001] This application is a continuation-in-part of U.S. Ser. No.10/273,975 filed Oct. 18, 2002, which claims the benefit of provisionalapplication U.S. Serial No. 60/342,015, filed Oct. 18, 2001, thedisclosures of which are hereby incorporated by reference herein in itsentirety.

FIELD OF THE INVENTION

[0002] The present invention provides novel human glucagon-likepeptide-1 (GLP-1) peptide mimics, which duplicate the biologicalactivity of the native peptide, exhibit increased stability toproteolytic cleavage as compared to GLP-1 native sequences, and thus areuseful for the amelioration of the diabetic condition.

BACKGROUND OF THE INVENTION

[0003] GLP-1 is an important gut hormone with regulatory function inglucose metabolism and gastrointestinal secretion and metabolism. HumanGLP-1 is a 30 amino acid residue peptide originating frompreproglucagon, which is synthesized for example, in the L-cells in thedistal ileum, in the pancreas and in the brain. Processing ofpreproglucagon to yield GLP-1(7-36)amide and GLP-2 occurs mainly in theL-cells. GLP-1 is normally secreted in response to food intake, inparticular carbohydrates and lipids stimulate GLP-1 secretion. GLP-1 hasbeen identified as a very potent and efficacious stimulator for insulinrelease. GLP-1 lowers glucagon concentration, slows gastric emptying,stimulates insulin biosynthesis and enhances insulin sensitivity (Nauck,1997, Horm. Metab. Res. 47:1253-1258). GLP-1 also enhances the abilityof the B-cells to sense and respond to glucose in subjects with impairedglucose tolerance (Byrne, Eur. J. Clin. Invest., 28:72-78, 1998). Theinsulinotropic effect of GLP-1 in humans increases the rate of glucosemetabolism partly due to increased insulin levels and partly due toenhanced insulin sensitivity (D'Alessio, Eur. J. Clin. Invest.,28:72-78, 1994). The above stated pharmacological properties of GLP-1make it a highly desirable therapeutic agent for the treatment oftype-II diabetes. Additionally, recent studies have shown that infusionsof slightly supraphysiological amounts of GLP-1 significantly enhancesatiety and reduce food intake in normal subjects (Flint, A., Raben, A.,Astrup, A. and Holst, J. J., J. Clin. Invest, 101:515-520, 1998;Gutswiller, J. P., Goke, B., Drewe, J., Hildebrand, P., Ketterer, S.,Handschin, D., Winterhaider, R., Conen, D and Beglinger, C. Gut44:81-86, 1999;). The effect on food intake and satiety has also beenreported to be preserved in obese subjects (Naslund, E., Barkeling, B.,King, N., Gutniak, M., Blundell, J. E., Holst, J. J., Rossner, S., andHellstrom, P. M., Int. J. Obes. Relat. Metab. Disord., 23:304-311,1999). In the above-cited studies a pronounced effect of GLP-1 ongastric emptying was also suspected to occur. Gastric emptying resultsin post-prandial glucose excursions. It has also been shown that inaddition to stimulation of insulin secretion, GLP-1 stimulates theexpression of the transcription factor IDX-1 while stimulating B-cellneogenesis and may thereby be an effective treatment and/or preventiveagent for diabetes (Stoffers, D. A., Kieffer, T. J. Hussain, M. A.,Drucker, D. J., Bonner-Weir, S., Habener, J. F. and Egan, J. M.Diabetes, 40:741-748, 2000). GLP-1 has also been shown to inhibitgastric acid secretion (Wettergren, A., Schjoldager, B., Mortensen, P.E., Myhre, J., Christiansen, J., Holst, J. J., Dig. Dis. Sci.,38:665-673, 1993), which may provide protection against gastric ulcers.

[0004] GLP-1 is an incretin hormone, for example, an intestinal hormonethat enhances meal-induced insulin secretion (Holst, J. J., Curr. Med.Chem., 6:1005-1017, 1999). It is a product of the glucagon gene encodingproglucagon. This gene is expressed not only in the A-cells of thepancreas but also in the endocrine L-cells of the intestinal mucosa.Proglucagon is a peptide (protein) containing 160 amino acids. Furtherprocessing of proglucagon results in the generation of a) glucagon, b)an N-terminal, presumably inactive fragment, and c) a large C-terminalfragment commonly referred as “the major proglucagon fragment”. Thisfragment is considered to be biologically inactive. Even though thisfragment is present in both pancreas and in the L-cells of the gut, itis only in the intestines the breakdown products of the “the majorproglucagon fragment” resulting in two highly homologous peptidescommonly referred as GLP-1 and GLP-2 are observed. These two peptideshave important biological activities. As such, the amino acid sequenceof GLP-1, which is present in the L-cells, is identical to the 78-107portion of proglucagon.

[0005] The present invention provides novel GLP-1 peptide mimics thatduplicate the biological activity of the native peptide and thus areuseful for the amelioration of the diabetic condition.

[0006] Presently, therapy involving the use of GLP-1-type molecules haspresented a significant problem because the serum half-life of suchpeptides is quite short. For example, GLP-1(7-37) has a serum half-lifeof only 3 to 5 minutes. Thus there exists a critical need forbiologically active GLP-1 mimics that possess extended pharmacodynamicprofiles.

SUMMARY OF THE INVENTION

[0007] In accordance with the present invention, synthetic isolatedpolypeptides are provided which have the structure of Formula I

A-X_(aa1)—X_(aa2)—X_(aa3)—X_(aa4)—X_(aa5)—X_(aa6)—X_(aa7)—X_(aa8)—X_(aa9)—Y-Z-B  I

[0008] wherein,

[0009] X_(aa1-9) is a naturally or nonnaturally occurring amino acidresidue;

[0010] Y and Z are amino acid residues;

[0011] wherein one of the substitutions at the alpha-carbon atoms of Yand Z may each independently be substituted with a primary substituentgroup selected from the group consisting of hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl,heterocyclylalkyl said primary substituent optionally being substitutedwith a secondary substituent selected from a cycloalkyl, heterocyclyl,aryl or heteroaryl group; any of said primary or secondary substituentsmay further be substituted with one or more of, hydrogen, alkyl,cycloalkyl, arylalkyl, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl,halo, hydroxy, mercapto, nitro, cyano, amino, acylamino, azido,guanidino, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl,acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy,heterocycleoxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl,mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl,guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl orphosphonic group; wherein, the primary or secondary substitutents mayoptionally be bridged by covalent bonds to form one or more fused cyclicor heterocyclic systems with each other;

[0012] wherein, the other substitution at the alpha-carbon of Y may besubstituted with hydrogen, alkyl, aminoalkyl, hydroxyalkyl orcarboxyalkyl;

[0013] wherein, the other substitution at the alpha-carbon of Z may besubstituted with hydrogen, alkyl, aminoalkyl, hydroxyalkyl orcarboxyalkyl;

[0014] A and B are optionally present;

[0015] wherein A is present and A is hydrogen, an amino acid or peptidecontaining from about 1 to about 15 amino acid residues, an R group, anR—C(O) (amide) group, a carbamate group RO—C(O), a urea R₄R₅N—C(O), asulfonamido R—SO₂, or a R₄R₅N—SO₂;

[0016] wherein R is selected from the group consisting of hydrogen,alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl,aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl andheteroaryloxyalkyl;

[0017] wherein R₄ and R₅ are each independently selected from the groupconsisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl,aryloxyalkyl, heteroarylalkyl and heteroaryloxyalky;

[0018] wherein the alpha-amino group of X_(aa1) is substituted with ahydrogen or an alkyl group, said alkyl group may optionally form a ringwith A;

[0019] wherein B is present and B is OR₁, NR₁R₂, or an amino acid orpeptide containing from 1 to 15 amino acid residues, preferably 1 to 10,more preferably 1 to 5 terminating at the C-terminus as a carboxamide,substituted carboxamide, an ester, a free carboxylic acid or anamino-alcohol;

[0020] wherein R₁ and R₂ are independently chosen from hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl,heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl orheteroaryloxyalkyl.

[0021] Preferred substitutions upon the alpha-carbon atoms of Y and Zare selected from the group consisting of heteroarylarylmethyl,arylheteroarylmethyl or biphenylmethyl forming biphenylalanine residues,any of which is also optionally substituted with one or more, hydrogen,alkyl, cycloalkyl, arylalkyl, aryl, heterocyclyl, heteroaryl, alkenyl,alkynyl, halo, hydroxy, mercapto, nitro, cyano, amino, acylamino, azido,guanidino, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl,acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy,heterocycleoxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl,mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl,guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl andphosphonic group.

[0022] Further embodiments include isolated polypeptides wherein theother substitution at the alpha-carbon of Y is substituted withhydrogen, methyl or ethyl; and wherein, the other substitution at thealpha-carbon of Z is substituted with hydrogen, methyl or ethyl.

[0023] Further embodiments include isolated polypeptides as describedabove wherein

[0024] X_(aa1) is naturally or nonnaturally occurring amino acid residuein which one of the substitutions at the alpha-carbon is a primarysubstituent selected from the group consisting of heterocyclylalkyl,heteroaryl, heteroarylkalkyl and arylalkyl, said primary substituentoptionally being substituted with secondary substituent selected fromheteroaryl or heterocyclyl; and in which the other substitution at thealpha-carbon is hydrogen or alkyl;

[0025] X_(aa2) is naturally or nonnaturally occurring amino acid residuein which one of the substitutions at the alpha-carbon is an alkyl orcycloalkyl where the alkyl group may optionally form a ring with thenitrogen of X_(aa2); and wherein the other substitution at thealpha-carbon is hydrogen or alkyl;

[0026] X_(aa3) is a naturally or nonnaturally occurring amino acidresidue in which one of the substitutions at the alpha-carbon isselected from the group consisting of a carboxyalkyl, bis-carboxyalkyl,sulfonylalkyl, heteroalkyl and mercaptoalkyl; and wherein the othersubstitution at the alpha-carbon is hydrogen or alkyl;

[0027] X_(aa4) is a naturally or nonnaturally occurring amino acidresidue in which the alpha-carbon is not substituted, or in which one ofthe substitutions at the alpha-carbon is selected from the groupconsisting of aminoalkyl, carboxyalkyl heteroarylalkyl andheterocycylalkyl;

[0028] X_(aa5) is a naturally or nonnaturally occurring amino acidresidue in which one of the substitutions at the alpha-carbon is analkyl or hydroxyalkyl, and in which the other substitution at thealpha-carbon is hydrogen or alkyl;

[0029] X_(aa6) is a naturally or nonnaturally occurring amino acidresidue in which one of the substitutions at the alpha-carbon isselected from the group consisting of alkyl, aryl, heteroaryl,heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl andheteroarylalkyl group, and wherein the other substitution at thealpha-carbon is hydrogen or alkyl;

[0030] X_(aa7) is a naturally or nonnaturally occurring amino acidresidue in which one of the substitutions at the alpha-carbon is ahydroxylalkyl group;

[0031] X_(aa8) is a naturally or nonnaturally occurring amino acidresidue in which one of the substitutions at the alpha-carbon isselected from the group consisting of alkyl, hydroxylalkyl,heteroarylalkyl and carboxamidoalkyl, and in which the othersubstitution at the alpha-carbon is hydrogen or alkyl;

[0032] X_(aa9) is a naturally or nonnaturally occurring amino acidresidue in which one of the substitutions at alpha-carbon is selectedfrom the group consisting of carboxylalkyl, bis-carboxylalkyl,carboxylaryl, sulfonylalkyl, carboxylamidoalkyl and heteroarylalkyl; andwherein

[0033] A is hydrogen, an amino acid or peptide containing from about 1to about 5 amino acid residues, an R group, an R—C(O) amide group, acarbamate group RO—C(O), a urea R₄R₅N—C(O), a sulfonamido R—SO₂ or aR₄R₅N—SO₂.

[0034] Preferred are isolated peptides wherein

[0035] X_(aa1) is an amino acid residue selected from the groupconsisting of L-His, D-His, L-N-Methyl-His, D-N-Methyl-His,L-4-ThiazolylAla and D-4-ThiazolylAla;

[0036] X_(aa2) is an amino acid residue selected from the groupconsisting of L-Ala, D-Ala, L-Pro, Gly, D-Ser, D-Asn, L-N-Methyl-Ala,D-N-Methyl-Ala, L-4-ThioPro, L-Pro(t-4-OH), L-2-Pip, L-2-Azt, Aib, S— orR-Iva and Acc₃;

[0037] X_(aa3) is an amino acid residue selected from the groupconsisting of L-Glu, L-N-Methyl-Glu, L-Asp, D-Asp, L-His, L-Gla, L-Adp,L-Cys and L-4-ThiazolylAla;

[0038] X_(aa4) is an amino acid residue selected from the groupconsisting of Gly, L-His, L-Lys and L-Asp;

[0039] X_(aa5) is an amino acid residue selected from the groupconsisting of L-Thr, D-Thr, L-Nle, L-Met, L-Nva and L-Aoc;

[0040] X_(aa6) is an amino acid residue selected from the groupconsisting of L-Phe, L-Tyr, L-Tyr(Bzl), Tyr(3-NO₂), L-Nle, L-Trp,L-Phe(penta-Fluoro), D-Phe(penta-Fluoro), Phe(2-Fluoro), Phe(3-Fluoro),Phe(4-Fluoro), Phe(2,3-di-Fluoro), Phe(3,4-di-Fluoro),Phe(3,5-di-Fluoro), L-Phe(2,6-di-Fluoro), Phe(3,4,5-tri-Fluoro),Phe(2-Iodo), Phe(2-OH), Phe(2-OMethyl), Phe(3-OMethyl), Phe(3-Cyano),Phe(2-Chloro), Phe(2-NH₂), Phe(3-NH₂), Phe(4-NH₂), Phe(4-NO₂),Phe(4-Methyl), Phe(4-Allyl), Phe(n-butyl), Phe(4-Cyclohexyl),Phe(4-Cyclohexyloxy), Phe(4-Phenyloxy), 2-NaphthylAla, 2-PyridylAla,L-4-ThiazolylAla, L-2-Thi, L-(α-Me-Phe, D-α-Me-Phe, L-α-Et-Phe,D-α-Et-Phe, L-α-Me-Phe(2-Fluoro), D-α-Me-Phe(2-Fluoro),L-α-Me-Phe(2,3-di-Fluoro), D-α-Me-Phe(2,3-di-Fluoro),L-α-Me-Phe(2,6-di-Fluoro), D-α-Me-Phe(2,6-di-Fluoro),L-α-Me-Phe(penta-Fluoro) and D-α-Me-Phe(penta-Fluoro);

[0041] X_(aa7) is an amino acid residue selected from the groupconsisting of L-Thr, D-Thr, L-Ser and L-hSer;

[0042] X_(aa8) is an amino acid residue selected from the groupconsisting of L-Ser, L-hSer, L-His, L-Asn and L-α-Me-Ser; and

[0043] X_(aa9) is an amino acid residue selected from the groupconsisting of L-Asp, L-Glu, L-Gla, L-Adp, L-Asn and L-His.

[0044] Additional embodiments include those wherein

[0045] Y is selected from the group consisting of L-Bip, D-Bip,L-Bip(2-Me), D-Bip(2-Me), L-Bip(2′-Me), L-Bip(2-Et), D-Bip(2-Et),L-Bip(3-Et), L-Bip(4-Et), L-Bip(2-n-Propyl), L-Bip(2-n-Propyl, 4-OMe),L-Bip(2-n-Propyl,2′-Me), L-Bip(3-Me), L-Bip(4-Me), L-Bip(2,3-di-Me),L-Bip(2,4-di-Me), L-Bip(2,6-di-Me), L-Bip(2,4-di-Et), L-Bip(2-Me,2′-Me), L-Bip(2-Et, 2′-Me), L-Bip(2-Et, 2′-Et), L-Bip(2-Me, 4-OMe),L-Bip(2-Et,4-OMe), D-Bip(2-Et,4-OMe), L-Bip(3-OMe), L-Bip(4-OMe),L-Bip(2,4,6-tri-Me), L-Bip(2,3-di-OMe), L-Bip(2,4-di-OMe),L-Bip(2,5-di-OMe), L-Bip(3,4-di-OMe), L-Bip(2-Et,4,5-di-OMe),L-Bip(3,4-Methylene-di-oxy), L-Bip(2-Et, 4,5-Methylene-di-oxy),L-Bip(2-CH₂OH, 4-OMe), L-Bip(2-Ac), L-Bip(3-NH—Ac), L-Bip(4-NH—Ac),L-Bip(2,3-di-Chloro), L-Bip(2,4-di-Chloro), L-Bip(2,5-di-Chloro),L-Bip(3,4-di-Chloro), L-Bip(4-Fluoro), L-Bip(3,4-di-Fluoro),L-Bip(2,5-di-Fluoro), L-Bip(3-n-Propyl), L-Bip(4-n-Propyl),L-Bip(2-iso-Propyl), L-Bip(3-iso-Propyl), L-Bip(4-iso-Propyl),L-Bip(4-tert-Butyl), L-Bip(3-Phenyl), L-Bip(2-Chloro), L-Bip(3-Chloro),L-Bip(2-Fluoro), L-Bip(3-Fluoro), L-Bip(2-CF₃), L-Bip(3-CF₃),L-Bip(4-CF₃), L-Bip(3-NO₂), L-Bip(3-OCF₃), L-Bip(4-OCF₃), L-Bip(2-OEt),L-Bip(3-OEt), L-Bip(4-OEt), L-Bip(4-SMe), L-Bip(2-OH), L-Bip(3-OH),L-Bip(4-OH), L-Bip(2-CH₂—COOH), L-Bip(3-CH₂—COOH), L-Bip(4-CH₂—COOH),L-Bip(2-CH₂—NH₂), L-Bip(3-CH₂—NH₂), L-Bip(4-CH₂—NH₂), L-Bip(2-CH₂—OH),L-Bip(3-CH₂—OH), L-Bip(4-CH₂—OH), L-Phe[4-(1-propargyl)],L-Phe[4-(1-propenyl)], L-Phe[4-n-Butyl], L-Phe[4-Cyclohexyl],Phe(4-Phenyloxy), L-Phe(penta-Fluoro),L-2-(9,10-Dihydrophenanthrenyl)-Ala, 4-(2-Benzo(b)furan)-Phe,4-(4-Dibenzofuran)-Phe, 4-(4-Phenoxathiin)-Phe,4-(2-Benzo(b)thiophene)-Phe, 4-(3-thiophene)-Phe, 4-(3-Quinoline)-Phe,4-(2-Naphthyl)-Phe, 4-(1-Naphthyl)-Phe,4-(4-(3,5-dimethylisoxazole))-Phe, 4-(2,4-dimethoxypyrimidine)-Phe,homoPhe, Tyr(Bzl), Phe(3,4-di-Chloro), Phe(4-Iodo), 2-Naphthyl-Ala,L-α-Me-Bip and D-α-Me-Bip;

[0046] Z is selected from the group consisting of L-Bip, D-Bip,L-Bip(2-Me), D-Bip(2-Me), L-Bip(2′-Me), L-Bip(2-Et), D-Bip(2-Et),L-Bip(3-Me), L-Bip(4-Me), L-Bip(3-OMe), L-Bip(4-OMe), L-Bip(4-Et),L-Bip(2-n-Propyl,2′-Me), L-Bip(2,4-di-Me), L-Bip(2-Me, 2′-Me),L-Bip(2-Me,4-OMe), L-Bip(2-Et,4-OMe), D-Bip(2-Et,4-OMe),L-Bip(2,6-di-Me), L-Bip(2,4,6-tri-Me), L-Bip(2,3,4,5,-tetra-Me),L-Bip(3,4-di-OMe), L-Bip(2,5-di-OMe), L-Bip(3,4-Methylene-di-oxy),L-Bip(3-NH—Ac), L-Bip(2-iso-Propyl), L-Bip(4-iso-Propyl),L-Bip(2-Phenyl), L-Bip(4-Phenyl), L-Bip(2-Fluoro), L-Bip(4-CF₃),L-Bip(4-OCF₃), L-Bip(2-OEt), L-Bip(4-OEt), L-Bip(4-SMe) ,L-Bip(2-CH₂—COOH), D-Bip(2-CH₂—COOH), L-Bip(2′-CH₂—COOH),L-Bip(3-CH₂—COOH), L-Bip(4-CH₂—COOH), L-Bip(2-CH₂—NH₂),L-Bip(3-CH₂—NH₂), L-Bip(4-CH₂—NH₂), L-Bip(2-CH₂—OH), L-Bip(3-CH₂—OH),L-Bip(4-CH₂—OH), L-Phe(3-Phenyl), L-Phe[4-n-Butyl], L-Phe[4-Cyclohexyl],Phe(4-Phenyloxy), L-Phe(penta-Fluoro),L-2-(9,10-Dihydrophenanthrenyl)-Ala, 4-(3-Pyridyl)-Phe,4-(2-Naphthyl)-Phe, 4-(1-Naphthyl)-Phe, 2-Naphthyl-Ala, 2-Fluorenyl-Ala,L-α-Me-Bip, D-α-Me-Bip, L-Phe(4-NO₂) and L-Phe(4-Iodo);

[0047] A is selected from the group consisting of H, Acetyl, β-Ala, Ahx,Gly, Asp, Glu, Phe, Lys, Nva, Asn, Arg, Ser. Thr, Val, Trp, Tyr,Caprolactam, L-Bip, L-Ser(Bzl), 3-PyridylAla, Phe(4-Me),Phe(penta-Fluoro), 4-Methylbenzyl, 4-Fluorobenzyl, n-propyl, n-hexyl,cyclohexylmethyl, 6-hydroxypentyl, 2-Thienylmethyl, 3-Thienylmethyl,penta-Fluorobenzyl, 2-naphthylmethyl, 4-biphenylmethyl,9-Anthracenylmethyl, benzyl, (S)-(2-amino-3-phenyl)propyl, methyl,2-aminoethyl and (S)-2-Aminopropyl; and

[0048] B is selected from the group consisting of OH, NH₂, Trp-NH₂,2-NaphthylAla-NH₂, Phe(penta-Fluoro)-NH₂, Ser(Bzl)-NH₂, Phe(4-NO₂)—NH₂,3-PyridylAla-NH₂, Nva-NH₂, Lys-NH₂, Asp-NH₂, Ser-NH₂, His-NH₂, Tyr-NH₂,Phe-NH₂, L-Bip-NH₂, D-Ser-NH₂, Gly-OH, β-Ala-OH, GABA-OH and APA-OH.

[0049] When A is not present, and X_(aa1) is an R group, an R—C(O)(amide) group, a carbamate group RO—C(O), a urea R₄R₅N—C(O), asulfonamido R—SO₂, or a R₄R₅N—SO₂; wherein

[0050] R is selected from the group consisting of hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl,heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl, heteroaryloxyalkyland heteroarylalkoxyalkyl; and wherein

[0051] R₄ and R₅ are each independently selected from the groupconsisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl,aryloxyalkyl, heteroarylalkyl and heteroaryloxyalky.

[0052] When B is not present and Z is OR₁, NR₁R₂ or an amino-alcohol;wherein

[0053] R₁ and R₂ are independently chosen from hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl,heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl orheteroaryloxyalkyl.

[0054] Preferred are isolated polypeptides wherein X_(aa1) (whereapplicable), X_(aa2) and X_(aa3) are N—H or N-alkylated, preferablyN-methylated amino acid residues.

[0055] Preferably the isolated polypeptide is a 10-mer to 15-mer andsuch polypeptide and binds to and activates the GLP-1 receptor.

[0056] The present invention also provides a method of making apolypeptide that mimics the activity of a polypeptide receptor agonist.

[0057] In accordance with the present invention, the synthetic isolatedpeptides described herein possess the ability to mimic the biologicalactivity of GLP peptides, with preference for mimicking GLP-1. Thesesynthetic peptide GLP-1 mimics exhibit desirable in-vivo properties,thus making them ideal therapeutic candidates for oral or parenteraladministration.

[0058] The present invention also provides an isolated polypeptideaccording to Formula 1, wherein the polypeptide is aGlucagon-Like-Peptide derivative, preferably a Glucagon-Like-Peptide-1derivative.

[0059] The present invention provides for compounds of formula I,pharmaceutical compositions employing such compounds and for methods ofusing such compounds. In particular, the present invention provides apharmaceutical composition comprising a therapeutically effective amountof a compound of formula I, alone or in combination with apharmaceutically acceptable carrier.

[0060] Further provided is a method for treating or delaying theprogression or onset of diabetes, especially type II diabetes, includingcomplications of diabetes, including retinopathy, neuropathy,nephropathy and delayed wound healing, and related diseases such asinsulin resistance (impaired glucose homeostasis), hyperglycemia,hyperinsulinemia, elevated blood levels of fatty acids or glycerol,obesity, hyperlipidemia including hypertriglyceridemia, Syndrome X,atherosclerosis and hypertension, and for increasing high densitylipoprotein levels, wherein a therapeutically effective amount of acompound of formula I is administered to a mammalian, e.g., human,patient in need of treatment.

[0061] The compounds of the invention can be used alone, in combinationwith other compounds of the present invention, or in combination withone or more other agent(s) active in the therapeutic areas describedherein.

[0062] In addition, a method is provided for treating diabetes andrelated diseases as defined above and hereinafter, wherein atherapeutically effective amount of a combination of a compound offormula I and at least one other type of therapeutic agent, such as anantidiabetic agent, a hypolipidemic agent or anti-obesity agent, isadministered to a human patient in need of treatment.

BRIEF DESCRIPTION OF THE DRAWINGS

[0063]FIG. 1 illustrates the effects of intravenous infusion of CompoundA and GLP-1 on plasma glucose in scGTT in rats.

[0064]FIG. 2 illustrates the effects of intravenous infusion of CompoundB and GLP-1 on plasma glucose in scGT in rats.

[0065]FIG. 3 illustrates the effects of subcutaneous injection ofCompound A and GLP-1 on plasma glucose in scGTT in rats.

[0066]FIG. 4 illustrates the effects of subcutaneous injection ofCompound B and GLP-1 on plasma glucose in scGTT in rats.

[0067]FIG. 5 illustrates the effects of subcutaneous injection ofCompound C on plasma glucose in an ipGTT model in rats.

[0068]FIG. 6 illustrates the effects of subcutaneous injection ofCompound D on plasma glucose in an ipGTT model in rats.

[0069]FIG. 7 illustrates the effects of subcutaneous injection of GLP-1on plasma glucose in an ipGTT model in rats.

DETAILED DESCRIPTION OF THE INVENTION

[0070] The following definitions apply to the terms as used throughoutthis specification, unless otherwise limited in specific instances.

[0071] Unless otherwise indicated, the term “amino-alcohol” as employedherein alone or as part of another group includes a natural orun-natural amino acid in which the carboxy group is replaced (reduced)to a methyl alcohol such as valinol, glycinol, alaninol, arylalaninol,heteroarylalaninol.

[0072] Unless otherwise indicated, the term “alkyl” as employed hereinalone or as part of another group includes both straight and branchedchain hydrocarbons, containing 1 to 40 carbons, preferably 1 to 20carbons, more preferably 1 to 8 carbons, in the normal chain, such asmethyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl,hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the variousbranched chain isomers thereof, and the like. Further, alkyl groups, asdefined herein, may optionally be substituted on any available carbonatom with one or more functional groups commonly attached to suchchains, such as, but not limited to alkyl, aryl, alkenyl, alkynyl,hydroxy, arylalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, arylalkyloxy,heteroaryloxy, heteroarylalkyloxy, alkanoyl, halo, hydroxyl, thio,nitro, cyano, carboxyl, carbonyl (

), carboxamido, amino, alkylamino, dialkylamino, amido, alkylamino,arylamido, heterarylamido, azido, guanidino, amidino, phosphonic,phosphinic, sulfonic, sulfonamido, haloaryl, CF₃, OCF₂, OCF₃, aryloxy,heteroaryl, cycloalkylalkoxyalkyl, cycloheteroalkyl and the like to formalkyl groups such as trifluoro methyl, 3-hydroxyhexyl, 2-carboxypropyl,2-fluoroethyl, carboxymethyl, cyanobutyl and the like.

[0073] Unless otherwise indicated, the term “alkenyl” as employed hereinalone or as part of another group includes both straight and branchedchain hydrocarbons, containing 2 to 40 carbons with one or more doublebonds, preferably 2 to 20 carbons with one to three double bonds, morepreferably 2 to 8 carbons with one to two double bonds, in the normalchain, such that any carbon may be optionally substituted as describedabove for “alkyl”.

[0074] Unless otherwise indicated, the term “alkynyl” as employed hereinalone or as part of another group includes both straight and branchedchain hydrocarbons, containing 2 to 40 carbons with one or more triplebonds, preferably 2 to 20 carbons with one to three triple bonds, morepreferably 2 to 8 carbons with one to two triple bonds, in the normalchain, such that any carbon may be optionally substituted as describedabove for “alkyl”.

[0075] Unless otherwise indicated, the term “cycloalkyl” as employedherein alone or as part of another group includes saturated or partiallyunsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groupscontaining 1 to 3 rings, appended or fused, including monocyclic alkyl,bicyclic alkyl and tricyclic alkyl, containing a total of 3 to 20carbons forming the rings, preferably 4 to 7 carbons, forming each ring;which may be fused to 1 aromatic ring as described for aryl, whichinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclodecyl, cyclododecyl, cyclohexenyl,

[0076] any of which groups may be optionally substituted through anyavailable carbon atoms with 1 or more groups selected from hydrogen,halo, haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl,trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkylalkyl, fluorenyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl,aryloxy, aryloxyalkyl, arylalkoxy, arylthio, arylazo, heteroarylalkyl,heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro,oxo, cyano, carboxyl, carbonyl

[0077] carboxamido, amino, substituted amino wherein the amino includes1 or 2 substituents (which are alkyl, aryl or any of the other arylcompounds mentioned in the definitions), amido, azido, guanidino,amidino, phosphonic, phosphinic, sulfonic, sulfonamido, thiol,alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio,alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl,alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy,alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl,arylsulfonylamino or arylsulfonaminocarbonyl, or any of alkylsubstituents as set out above.

[0078] The term “aryl” as employed herein alone or as part of anothergroup refers to monocyclic and bicyclic aromatic groups containing 6 to10 carbons in the ring portion (such as phenyl or naphthyl) and mayoptionally include one to three additional rings fused to “aryl” (suchas aryl, cycloalkyl, heteroaryl or heterocycloalkyl rings) and may beoptionally substituted through any available carbon atoms with 1 or moregroups selected from hydrogen, alkyl, halo, haloalkyl, alkoxy,haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl,cycloalkylalkyl, fluorenyl, heterocycloalkyl, heterocycloalkylalkyl,aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy,arylthio, arylazo, heteroarylalkyl, heteroarylalkenyl, heteroaryloxy,hetroarylalkyloxy, hetroarylalkyloxyalkyl, hydroxy, nitro, oxo, cyano,amino, substituted amino wherein the amino includes 1 or 2 substituents(which are alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl orany of the other aryl compounds mentioned in the definitions), thiol,alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio,alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl,cycloalyklaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl,heteroarylalkylaminocarbonyl alkoxycarbonyl, aminocarbonyl,alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino,arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino orarylsulfonaminocarbonyl, or any of alkyl substituents as set out above.

[0079] The term “arylalkyl” as used herein alone or as part of anothergroup refers to alkyl groups as defined above having an arylsubstituent, such as benzyl, phenethyl or naphthylpropyl, wherein saidaryl and/or alkyl groups may optionally be substituted as defined above.

[0080] The term “alkoxyl”, “aryloxyl”, “heteroaryloxy” “arylalkyloxy”,or “heteroarylalkyloxy” as employed herein alone or as part of anothergroup includes an alkyl or aryl group as defined above linked through anoxygen atom.

[0081] The term “heterocyclo”, “heterocycle” “heterocyclyl” or“heterocyclic”, as used herein, represents an unsubstituted orsubstituted stable 4-, 5-, 6- or 7-membered monocyclic ring system whichmay be saturated or unsaturated, and which consists of carbon atoms andfrom one to four heteroatoms selected from nitrogen, sulfur, oxygenand/or a SO or SO₂ group, wherein the nitrogen and sulfur heteroatomsmay optionally be oxidized, and the nitrogen heteroatom may optionallybe quaternized. The heterocyclic ring may be attached at any heteroatomor carbon atom which results in the creation of a stable structure.Examples of such heterocyclic groups include, but is not limited to,tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl,piperazinyl, oxopyrrolidinyl, oxopiperazinyl, oxopiperidinyl andoxadiazolyl. Optionally a heterocyclo group may be substituted with oneor more functional groups, such as those described for “alkyl” or“aryl”.

[0082] The term “heterocycloalkyl” as used herein alone or as part ofanother group refers to alkyl groups as defined above having aheterocycloalkyl substituent, wherein said “heterocyclo” and/or alkylgroups may optionally be substituted as defined above.

[0083] The term “heteroaryl” as used herein refers to a 5-, 6- or7-membered aromatic heterocyclic ring which contains one or moreheteroatoms selected from nitrogen, sulfur, oxygen and/or a SO or SO₂group. Such rings may be fused to another aryl or heteroaryl ring andinclude possible N-oxides; Examples of such heteroaryl groups include,but are not limited to, furan, pyrrole, thiophene, pyridine, isoxazole,oxazole, imidazole and the like. Optionally a heteroaryl group may besubstituted with one or more functional groups commonly attached to suchchains, such as those described for “alkyl” or “aryl”.

[0084] The term “heteroarylalkyl” as used herein alone or as part ofanother group refers to alkyl groups as defined above having aheteroaryl substituent, wherein said heteroaryl and/or alkyl groups mayoptionally be substituted as defined above.

[0085] The term “diabetes and related diseases or related conditions”refers to Type II diabetes, Type I diabetes, impaired glucose tolerance,obesity, hyperglycemia, Syndrome X, dysmetabolic syndrome, diabeticcomplications, and hyperinsulinemia.

[0086] The term “lipid-modulating” or “lipid lowering” agent as employedherein refers to agents that lower LDL and/or raise HDL and/or lowertriglycerides and/or lower total cholesterol and/or other knownmechanisms for therapeutically treating lipid disorders.

[0087] An administration of a therapeutic agent of the inventionincludes administration of a therapeutically effective amount of theagent of the invention. The term “therapeutically effective amount” asused herein refers to an amount of a therapeutic agent to treat orprevent a condition treatable by administration of a composition of theinvention. That amount is the amount sufficient to exhibit a detectabletherapeutic or preventative or ameliorative effect. The effect mayinclude, for example, treatment or prevention of the conditions listedherein. The precise effective amount for a subject will depend upon thesubject's size and health, the nature and extent of the condition beingtreated, recommendations of the treating physician, and the therapeuticsor combination of therapeutics selected for administration. Thus, it isnot useful to specify an exact effective amount in advance.

[0088] The peptides and analogs thereof described herein may be producedby chemical synthesis using various solid-phase techniques such as thosedescribed in G. Barany and R. B. Merrifield, “The Peptides: Analysis,Synthesis, Biology”; Volume 2—“Special Methods in Peptide Synthesis,Part A”, pp. 3-284, E. Gross and J. Meienhofer, Eds., Academic Press,New York, 1980; and in J. M. Stewart and J. D. Young, “Solid-PhasePeptide Synthesis”, 2^(nd) Ed., Pierce Chemical Co., Rockford, Ill.,1984. The preferred strategy for use in this invention is based on theFmoc (9-Fluorenylmethylmethyloxycarbonyl) group for temporary protectionof the α-amino group, in combination with the tert-butyl group fortemporary protection of the amino acid side chains (see for example E.Atherton and R. C. Sheppard, “The Fluorenylmethoxycarbonyl AminoProtecting Group”, in “The Peptides: Analysis, Synthesis, Biology”;Volume 9—“Special Methods in Peptide Synthesis, Part C”, pp. 1-38, S.Undenfriend and J. Meienhofer, Eds., Academic Press, San Diego, 1987.

[0089] The peptides can be synthesized in a stepwise manner on aninsoluble polymer support (also referred to as “resin”) starting fromthe C-terminus of the peptide. A synthesis is begun by appending theC-terminal amino acid of the peptide to the resin through formation ofan amide or ester linkage. This allows the eventual release of theresulting peptide as a C-terminal amide or carboxylic acid,respectively. Alternatively, in cases where a C-terminal amino alcoholis present, the C-terminal residue may be attached to2-Methoxy-4-alkoxybenzyl alcohol resin (SASRIN™, Bachem Bioscience,Inc., King of Prussia, Pa.) as described herein and, after completion ofthe peptide sequence assembly, the resulting peptide alcohol is releasedwith LiBH₄ in THF (see J. M. Stewart and J. D. Young, supra, p. 92).

[0090] The C-terminal amino acid and all other amino acids used in thesynthesis are required to have their α-amino groups and side chainfunctionalities (if present) differentially protected such that theα-amino protecting group may be selectively removed during thesynthesis. The coupling of an amino acid is performed by activation ofits carboxyl group as an active ester and reaction thereof with theunblocked α-amino group of the N-terminal amino acid appended to theresin. The sequence of α-amino group deprotection and coupling isrepeated until the entire peptide sequence is assembled. The peptide isthen released from the resin with concomitant deprotection of the sidechain functionalities, usually in the presence of appropriate scavengersto limit side reactions. The resulting peptide is finally purified byreverse phase HPLC.

[0091] The synthesis of the peptidyl-resins required as precursors tothe final peptides utilizes commercially available cross-linkedpolystyrene polymer resins (Novabiochem, San Diego, Calif.). Preferredfor use in this invention are4-(2′,4′-dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetyl-p-methylbenzhydrylamine resin (Rink amide MBHA resin) or p-benzyloxybenzylalcohol resin (HMP resin) to which the C-terminal amino acid may or maynot be already attached. If the C-terminal amino acid is not attached,its attachment may be achieved by DMAP-catalyzed esterification with theO-acylisourea or the HOAT active ester of the Fmoc-protected amino acidformed by its reaction with DIC or DIC/HOAT, respectively. Coupling ofthe subsequent amino acids can be accomplished using HOBT or HOAT activeesters produced from DIC/HOBT or DIC/HOAT, respectively.

[0092] The syntheses of the 11-mer peptide analogs described herein canbe carried out by using a peptide synthesizer, such as an AdvancedChemtech Multiple Peptide Synthesizer (MPS396) or an Applied BiosystemsInc. peptide synthesizer (ABI 433A). If the MPS396 was used, up to 96peptides were simultaneously synthesized. If the ABI 433A synthesizerwas used, individual peptides were synthesized sequentially. In bothcases the stepwise solid phase peptide synthesis was carried oututilizing the Fmoc/t-butyl protection strategy described herein. Thenon-natural non-commercial amino acids present at position 11 and atposition 10 were incorporated into the peptide chain in one of twomethods. In the first approach a Boc- or Fmoc-protected non-naturalamino acid was prepared in solution using appropriate organic syntheticprocedures. The resulting derivative was then used in the step-wisesynthesis of the peptide. Alternatively the required nonnatural aminoacid was built on the resin directly using synthetic organic chemistryprocedures. When a nonnatural non-commercial amino acid was needed forincorporation at position X_(aa6) or at any other X_(aa) position asneeded, the required Fmoc-protected nonnatural amino acid wassynthesized in solution. Such a {acute over ()}derivative was then usedin stepwise solid phase peptide synthesis.

[0093] Preferred for use in this invention are the Fmoc amino acidsderivatives shown below.

Orthogonally Protected Amino Acids Used in Solid Phase Synthesis

[0094]

Protected Amino Acid Used in Solid Phase Synthesis

[0095]

[0096] The peptidyl-resin precursors for their respective peptides maybe cleaved and deprotected using any of the standard proceduresdescribed in the literature (see, for example, D. S. King et al. Int. J.Peptide Protein Res. 36, 1990, 255-266). A preferred method for use inthis invention is the use of TFA in the presence of water and TIS asscavengers. Typically, the peptidyl-resin is stirred in TFA/water/TIS(94:3:3, v:v:v; 1 mL/100 mg of peptidyl resin) for 1.5-2 hrs at roomtemperature. The spent resin is then filtered off and the TFA solutionis concentrated or dried under reduced pressure. The resulting crudepeptide is either precipitated and washed with Et₂O or is redissolveddirectly into DMSO or 50% aqueous acetic acid for purification bypreparative HPLC.

[0097] Peptides with the desired purity can be obtained by purificationusing preparative HPLC, for example, on a Waters Model 4000 or aShimadzu Model LC-8A liquid chromatograph. The solution of crude peptideis injected into a YMC S5 ODS (20×100 mm) column and eluted with alinear gradient of MeCN in water, both buffered with 0.1% TFA, using aflow rate of 14-20 mL/min with effluent monitoring by UV absorbance at220 nm. The structures of the purified peptides can be confirmed byelectro-spray MS analysis.

[0098] The following abbreviations are employed in the Examples andelsewhere herein: Ph = phenyl Bn = benzyl i-Bu = iso-butyl Me = methylEt = ethyl Pr = n-propyl Bu = n-butyl TMS = trimethylsilyl TIS =Triisopropylsilane Et₂O = diethyl ether HOAc or AcOH = acetic acid MeCN= acetonitrile DMF = N,N- dimethylformamide EtOAc = ethyl acetate THF =tetrahydrofuran TFA = trifluoroacetic acid Et₂NH = diethylamine NMM =N-methyl morpholine NMP = N-methylpyrrolidone DCM = dichloromethanen-BuLi = n-butyllithium Pd/C = palladium on carbon PtO₂ = platinum oxideTEA = triethylamine min = minute(s) h or hr = hour(s) L = liter mL =milliliter μL = microliter g = gram(s) mg = milligram(s) mol = mole(s)mmol = millimole(s) meq = milliequivalent rt = room temperature sat orsat'd = saturated aq. = aqueous mp = melting point

[0099] Bip=biphenylalanine

[0100] LiBH₄=lithium borohydride

[0101] PyBOP reagent=benzotriazol-1-yloxy-tripyrrolidino phosphoniumhexafluorophosphate

[0102] DMAP=4-(dimethylamino)pyridine p0EDAC=3-ethyl-3′-(dimethylamino)propyl-carbodiimide hydrochloride (or1-[(3-(dimethyl)amino)propyl])-3-ethylcarbodiimide hydrochloride)

[0103] FMOC=fluorenylmethoxycarbonyl

[0104] Boc or BOC=tert-butoxycarbonyl

[0105] Cbz=carbobenzyloxy or carbobenzoxy or benzyloxycarbonyl

[0106] HOBT or HOBT•H₂O=1-hydroxybenzotriazole hydrate

[0107] HOAT=1-hydroxy-7-azabenzotriazole

[0108] TLC=thin laer chromatography

[0109] HPLC=high peformance liquid chromatography

[0110] LC/MS=high performace liquid chromatography/mass spectrometry

[0111] MS or Mass Sec=mass spectrometry

[0112] NMR=nuclear magnetic resonance

[0113] Those skilled in the art of peptide chemistry are aware thatamino acid residues occur as both D and L isomers, and that the instantinvention contemplates the use of either or a mixture of isomers foramino acid residues incorporated in the synthesis of the peptidesdescribed herein.

[0114] In one embodiment, the present invention provides a method ofmaking a polypeptide of formula

[0115] that mimics the activity of a polypeptide receptor agonist havinga message sequence and an address sequence. In this embodiment, theaddress sequence of the polypeptide confers the ability of a polypeptideto bind to a receptor and the message sequence is capable of inducingreceptor mediated signal transduction upon binding of the polypeptide tothe receptor. The method of making the polypeptide comprises replacingthe message sequence of a polypeptide receptor agonist with Y and Zwherein Y and Z are amino acid residues;

[0116] wherein one of the substitutions at the alpha-carbon atoms of Yand Z may each independently be substituted with a primary substituentgroup selected from the group consisting of hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl,heterocyclylalkyl said primary substituent optionally being substitutedwith a secondary substituent selected from a cycloalkyl, heterocyclyl,aryl or heteroaryl group; any of said primary or secondary substituentsmay further be substituted with one or more of, hydrogen, alkyl,cycloalkyl, arylalkyl, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl,halo, hydroxy, mercapto, nitro, cyano, amino, acylamino, azido,guanidino, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl,acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy,heterocycleoxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl,mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl,guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl orphosphonic group; wherein, the primary or secondary substitutents mayoptionally be bridged by covalent bonds to form one or more fused cyclicor heterocyclic systems with each other;

[0117] wherein, the other substitution at the alpha-carbon of Y may besubstituted with hydrogen, alkyl, aminoalkyl, hydroxyalkyl orcarboxyalkyl;

[0118] wherein, the other substitution at the alpha-carbon of Z may besubstituted with hydrogen, alkyl, aminoalkyl, hydroxyalkyl orcarboxyalkyl.

[0119] In a preferred embodiment, the present invention provides amethod of making a polypeptide that mimics the activity of an endogenouspolypeptide receptor agonist. In another preferred embodiment, thepolypeptide receptor agonist is GLP-1.

[0120] In another aspect, the method of making the polypeptide furthercomprises replacing the message sequence of the polypeptide with avariant message sequence capable of inducing receptor mediated signaltransduction. Variant message sequences can be made by replacing ormodifying one or more amino acid residues of a polypeptide receptoragonist message sequence.

EXAMPLE 1 Simultaneous Solid Phase Peptide Synthesis of GLP-1 11-merPeptide Mimics

[0121] Dipeptidyl resin, containing non-natural non-commercial aminoacid residues at positions 10 and 11, was prepared using the followingmanual procedure in a batch-wise mode before continuing peptide chainelongation utilizing the automated simultaneous synthesis protocol onthe MPS-396 peptide synthesizer. The synthesis of the Nα-Fmoc-protectedbiphenylalanine derivatives used in the manual couplings is described inExamples 8-10.

[0122] An amount of4-(2′,4′-dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetyl-p-methylbenzhydrylamine resin (Rink amide MBHA resin; loading: 0.5 mmol/g)sufficient to synthesize several 11-mer analogs, was swelled by washingwith DMF (4×10 mL/g, 5 minutes). The Fmoc group was then removed usingtwo treatments, 3 and 18 minutes each respectively, with 20% piperidinein DMF (10 mL/g). The resin was washed with DMF (4×10 mL/g) and NMP(4×10 mL/g). A 0.5 M solution of Fmoc-L-biphenylalanine-OH (2.0 eq.), oranalog thereof, and HOAt (2.0 eq.) in NMP was added to the resin,followed by a 1.0 M solution of DIC (2.05 eq.) in NMP. The resin wasthen shaken or vortexed for 16-24 hours. Coupling completion wasmonitored using a qualitative ninhydrin test. The resin was drained,washed with NMP (3×10 mL/g) and DMF (3×10 mL/g), and treated twice, 5and 20 minutes each respectively, with 20% acetic anhydride in DMF (8mL/g). After DMF washes (4×10 mL/g), a second manual coupling cycle wasthen performed as described above, starting from the removal of the Fmocgroup with 20% piperidine in DMF, and using either the same or adifferent Fmoc-protected biphenylalanine analog in the coupling step.This synthesis scheme produced the desired Fmoc-protecteddipeptidyl-Rink amide MBHA resin.

[0123] Similar dipeptidyl resins were also obtained by anotherprocedure, described in Examples 5-7, using solid phase Suzukicondensation reactions.

[0124] Such dipeptidyl-resins required for the synthesis of a set ofdesigned analogs were then used in the automated MPS synthesis of up to96 peptides per run in the following manner. The dipeptidyl-resins wereloaded as suspensions in dichloromethane/DMF (60:40) into the 96-wellreactor of an Advanced ChemTech MPS 396 synthesizer in volumescorresponding to 0.01-0.025 mmol (20-50 mg) of resin per reactor well.The reactor was placed on the instrument and drained. The wells werethen washed with DMF (0.5-1.0 mL, 3×2 min) and subjected to the numberof automated coupling cycles required to assemble the respective peptidesequences as determined by the pre-programmed sequence synthesis table.The detailed stepwise synthesis protocol used for a typical 0.01mmol/well simultaneous synthesis of 96 compounds is described below.This protocol was adapted for the simultaneous synthesis of arrays ofanalogs ranging from 12 to 96 per individual run. The general synthesisprotocol is depicted in Scheme I.

[0125] Prior to starting the synthesis, the following reagent solutionswere prepared and placed on the instrument as required: 1.5 M (15%)piperidine in DMF; 0.5 M DIEA in NMP; 0.36 M DIC in NMP; 1 M (10%)acetic anhydride in DMF. The required Fmoc-protected amino acids wereprepared as 0.36 M solutions in 0.36 M HOAt/NMP and placed into theappropriate positions in the 32-position amino acid rack.

[0126] The Fmoc-protected dipeptidyl-resin prepared above wasdeprotected by treating with 1.5 M (15%) piperidine in DMF (0.6 mL; 1×3minutes; 1×18 minutes). The resin was then washed with DMF (4×0.5 mL),DMF/EtOH (80:20) (1×0.5 mL) and NMP (3×0.5 mL).

[0127] Coupling of the next amino acid residue, typicallyFmoc-Asp(OtBu)-OH or another Fmoc-amino acid with appropriate orthogonalprotection if required, was carried out by automated addition of a 0.36M solution of the appropriate Fmoc-amino acid (0.072 mmol, 7.2 eq.) andHOAt (7.2 eq.) in NMP (0.2 mL) to all 96 wells. This was followed byaddition to all 96 wells of a 0.36 M solution of DIC (0.072 mmol, 7.2eq.) in NMP (0.2 mL). The coupling was allowed to proceed for 2 hrs.After reactor draining by nitrogen pressure (3-5 psi) and washing thewells with NMP (1×0.5 mL), the coupling was repeated as described above.At the end of the coupling cycle, the wells were treated with 1M aceticanhydride in DMF (1×0.5 mL, 30 min.) and finally washed with DMF (3×0.5mL).

[0128] The next coupling cycle started with the removal of the Fmocgroup as described above, and involved the coupling of eitherFmoc-Ser(tBu)-OH or of a different Fmoc-amino acid as required by thesequence substitutions desired at this position. The coupling wascarried out in a manner identical to that described forFmoc-Asp(OtBu)-OH. The next coupling step was carried out in the sameway to incorporate either Fmoc-Thr(tBu)-OH or any of the other selectedFmoc-amino acids into this sequence position as required.

[0129] The next Fmoc-amino acid (for example Fmoc-Phe-OH) was coupled asdescribed above. For sequences requiring incorporation of a novelnon-commercially available aromatic or non-aromatic amino acid analog atthis step, the coupling was modified as follows: after Fmoc deprotectionin the usual manner, the Fmoc-amino acid (5 eq.) and HOAt (5 eq.) wereadded manually as a 0.36 M solution in NMP (0.139 mL). The 0.36 Msolution of DIC in NMP (0.139 mL) was then added by the instrument andthe coupling was allowed to proceed for 16-24 hrs. The coupling was notrepeated in this case. After the usual post-coupling washes, thepeptidyl-resins were capped with acetic anhydride as described.

[0130] The next coupling step involved either Fmoc-Thr(tBu)-OH orsubstitution analogs as required by sequence replacements at thisposition. The coupling was performed as described for the initial MPScoupling of Fmoc-Asp(OtBu)-OH and its analogs. This identical couplingprotocol was repeated four additional times in order to complete thesequence assembly of the desired 96 11-mer peptide analogs. For thecoupling of commercially and non-commercially available non-naturalamino acids needed at a certain sequence position, a single couplingprotocol similar to that described above for the novel amino acid atposition 6 (X_(aa6)) was used.

[0131] Finally, the Fmoc group was removed with 20% piperidine in DMF asdescribed above, and the peptidyl-resins were washed with DMF (4×0.5 mL)and DCM (4×0.5 mL). They were then dried on the reactor block byapplying a constant pressure of nitrogen gas (5 psi) for 10-15 min.

Cleavage/Deprotection

[0132] The desired peptides were cleaved/deprotected from theirrespective peptidyl-resins by treatment with a TFA cleavage mixture asfollows. A solution of TFA/water/tri-isopropylsilane (94:3:3) (1.0 mL)was added to each well in the reactor block, which was then vortexed for2 hrs. The TFA solutions from the wells were collected by positivepressure into pre-tared vials located in a matching 96-vial block on thebottom of the reactor. The resins in the wells were rinsed twice with anadditional 0.5 mL of TFA cocktail and the rinses were combined with thesolutions in the vials. These were dried in a SpeedVac™ (Savant) toyield the crude peptides, typically in >100% yields (20-40 mgs). Thecrude peptides were either washed with ether or more frequentlyre-dissolved directly in 2 mL of DMSO or 50% aqueous acetic acid forpurification by preparative HPLC as follows.

Preparative HPLC Purification of the Crude Peptides

[0133] Preparative HPLC was carried out either on a Waters Model 4000 ora Shimadzu Model LC-8A liquid chromatograph. Each solution of crudepeptide was injected into a YMC S5 ODS (20×100 mm) column and elutedusing a linear gradient of MeCN in water, both buffered with 0.1% TFA. Atypical gradient used was from 20% to 70% 0.1% TFA/MeCN in 0.1%TFA/water over 15 min. at a flow rate of 14 mL/min with effluent UVdetection at 220 nm. The desired product eluted well separated fromimpurities, typically after 10-11 min., and was usually collected in asingle 10-15 mL fraction on a fraction collector. The desired peptideswere obtained as amorphous white powders by lyophilization of their HPLCfractions.

HPLC Analysis of the Purified Peptides

[0134] After purification by preparative HPLC as described above, eachpeptide was analyzed by analytical RP-HPLC on a Shimadzu LC-10AD orLC-10AT analytical HPLC system consisting of: a SCL-10A systemcontroller, a SIL-10A auto-injector, a SPD10AV or SPD-M6A UV/VISdetector, or a SPD-M10A diode array detector. A YMC ODS S3 (4.6×50 mm)column was used and elution was performed using one of the followinggradients: 10-70% B in A over 8 min, 2.5 mL/min. (method A); 5-80% B inA over 8 min, 2.5 mL/min. (method B); 5-70% B in A over 8 min., 2.5mL/min. (method C); 25-75% B in A over 8 min, 2.5 mL/min (method D);20-75% B in A over 8 min, 2.5 mL/min. (method E); 15-70% B in A over 8min, 2.5 mL/min. (method F); 10-90% B in A over 8 min, 2.5 mL/min.(method G); 20-65% B in A over 8 min, 2.5 mL/min. (method H); 5-90% B inA over 8 min., 2.0 mL/min. (method I); 5-90% B in A over 8 min., 2.5mL/min. (method J); 20-80% B in A over 8 min., 2.5 mL/min. (method K);10-100% B in A over 8 min., 2.5 mL/min. (method L); 10-75% B in A over 8min., 2.5 mL/min. (method M). Mobile phase A: 0.1% TFA/water; mobilephase B: 0.1% TFA/acetonitrile. The purity was typically >90%.

Characterization by Mass Spectrometry

[0135] Each peptide was characterized by electrospray mass spectrometry(ES-MS) either in flow injection or LC/MS mode. Finnigan SSQ7000 singlequadrupole mass spectrometers (ThermoFinnigan, San Jose, Calif.) wereused in all analyses in positive and negative ion electrospray mode.Full scan data was acquired over the mass range of 300 to 2200 amu for ascan time of 1.0 second. The quadrupole was operated at unit resolution.For flow injection analyses, the mass spectrometer was interfaced to aWaters 616 HPLC pump (Waters Corp., Milford, Mass.) and equipped with anHTS PAL autosampler (CTC Analytics, Zwingen, Switzerland). Samples wereinjected into a mobile phase containing 50:50 water:acetonitrile with0.1% ammonium hydroxide. The flow rate for the analyses was 0.42 mL/min.and the injection volume 6 μl. A ThermoSeparations Constametric 3500liquid chromatograph (ThermoSeparation Products, San Jose, Calif.) andHTS PAL autosampler were used for LC/MS analyses. Chromatographicseparations were achieved employing a Luna C₁₈, 5 micron column, 2×30 mm(Phenomenex, Torrance, Calif.). The flow rate for the analyses was 1.0mL/min and column effluent was split, so that the flow into theelectrospray interface was 400 μl/min. A linear gradient from 0% to 100%B in A over 4 minutes was run, where mobile phase A was 98:2water:acetonitrile with 10 mM ammonium acetate and mobile phase B was10:90 water:acetonitrile with 10 mM ammonium acetate. The UV responsewas monitored at 220 nm. The samples were dissolved in 200 μl 50:50H₂O:MeCN (0.05% TFA). The injection volume was 5 μl.

[0136] In all cases, the experimentally measured molecular weight waswithin 0.5 Daltons of the calculated mono-isotopic molecular weight.

EXAMPLE 2 Synthesis of N-acylated and N-alkylated 11-mer Peptide Analogs

[0137] (A) General Procedure for the Synthesis of N-alkylated 11-merPeptide Analogs by Reductive Alkylation.

[0138] The synthesis of N-alkylated 11-mer peptide analogs was startedfrom the protected intermediate 11-mer peptidyl-resin (1) (0.025 mmol),which was prepared by the general method described herein. The Fmocgroup was removed using the procedure described in that method, to yieldthe protected resin intermediate 2. This was swollen in DMF, washed 3times with 1% AcOH/DMF, and then treated with 2-20 eq. of aldehyde orN-Boc-protected aminoaldehyde (see synthesis below), dissolved in 1%AcOH/DMF (or CH₂Cl₂) (1 M), and the same excess amount of Na(AcO)₃BH asthat of the aldehyde. After overnight reaction, the resin was drained,washed with DMF and DCM, 3 times each, and dried. The reductivelyalkylated peptide (4) was cleaved and deprotected by treatment withTFA/tri-isopropylsilane/water (90:5:5, v:v:v; 1-2 mL) for 2 hrs. Theresin was filtered off and rinsed with 1 mL of cleavage solution, whichwas combined with the filtrate and dried in a SpeedVac™ (Savant) toyield the crude product. This was purified by preparative HPLC asdescribed in the general peptide synthesis method outlined herein. Thepurity and identity of the desired products were confirmed by analyticalHPLC and electrospray MS.

[0139] N-Boc-protected aminoaldehydes were synthesized using Castro'sprocedure (Fehrentz, J. A., and Castro, B., Synthesis, 1983, 676-678) asfollows. The Boc-protected amino acid (2.0 mmol) was dissolved in 5 mLDCM. BOP reagent (1.1 eq.) and DIEA (1.15 eq) were added. After 5minutes, a solution of N,O-dimethylhydroxylamine (1.2 eq) and DIEA (1.3eq) in 5 mL DCM was added. The reaction mixture was stirred for 2 hrs,diluted with DCM (30 mL), and washed with 2N HCl (3×), sat. NaHCO₃ (3×)and brine (1×). The organic extracts were dried over MgSO₄, filtered andevaporated to dryness to yield the Weinreb amide. This was thendissolved in ether or THF (10 mL/mmol)) and reacted with a 1M solutionof LiAlH₄ in THF (2 mL/mmol of hydroxamate) for 30 minutes. The reactionmixture was quenched with 5 mL of 0.35 M KHSO₄, and diluted with ether(20 mL). The aqueous phase was separated and extracted with ether (3×20mL). The combined ether extracts were washed with 2N HCl (2×), sat.NaHCO₃ (2×) and brine (1×), dried over MgSO₄, filtered and evaporated todryness to yield the Boc-protected aldehyde in 20-30% yield. Thealdehyde was characterized by ¹H-NMR and electrospray MS, and was usedin the reductive alkylation step without further purification.

[0140] (B) General procedure for the synthesis of N-acylated 11-merpeptide analogs.

[0141] Similarly, the synthesis of the N-acylated 11-mer peptide analogswas started from the protected 11-mer peptidyl-resin intermediate (1)(0.025 mmol), prepared as described herein. The Fmoc group was removedusing the procedure described herein, and the resulting resinintermediate 2 was coupled with the relevant Fmoc-protected amino acidor carboxylic acid using the coupling protocol described in the generalmethod described herein. In cases where the appropriate anhydride wasavailable, the N-acylation was performed using 10 eq. of the anhydridein NMP. The resulting 12-mer analogs (3) were cleaved/deprotected andpurified by prep. HPLC by the general method described herein.

[0142] (C) General procedure for the synthesis of N-carbamatederivatives of 11-mer peptide analogs.

[0143] The synthesis of N-carbamate derivatives of 11-mer peptideanalogs may be started from the protected 11-mer peptidyl-resinintermediate (1) (0.025 mmol), prepared as described herein. The Fmocgroup is removed using the procedure described herein, and the resultingresin intermediate 2 is allowed to react with the relevant chloroformatein the presence of an appropriate base such as a tertiary amine, or witha di-carbonate or an activated carbonate such as p-nitrophenyl or phenylcarbonate. Similarly, N-carbamate derivatives of 10-mer peptide analogsmay be prepared starting from a protected 10-mer peptidyl-resinintermediate, Fmoc removal and reaction of the resulting peptidyl-resinintermediate with the relevant chloroformate, di-carbonate or activatedcarbonate.

[0144] (D) General procedure for the synthesis, of N-urea derivatives of11-mer peptide analogs.

[0145] The synthesis of N-urea derivatives of 11-mer peptide analogs maybe started from the protected 11-mer peptidyl-resin intermediate (1)(0.025 mmol), prepared as described herein. The Fmoc group is removedusing the procedure described herein, and the resulting resinintermediate 2 is allowed to react with the relevant isocyanateprepared, for example, as in K. Burgess et al., J. Am. Chem. Soc. 1997,119, 1556-1564; alternatively, the resin intermediate 2 may be allowedto react with the relevant carbamyl chloride. Similarly, N-ureaderivatives of 10-mer peptide analogs may be prepared starting from aprotected 10-mer peptidyl-resin intermediate, Fmoc removal and reactionof the resulting peptidyl-resin intermediate with the relevantisocyanate or carbamyl chloride.

[0146] (E) General procedure for the synthesis of N-sulfonamides of11-mer peptide analogs.

[0147] The synthesis of N-sulfonamides of 11-mer peptide analogs may bestarted from the protected 11-mer peptidyl-resin intermediate (1) (0.025mmol), prepared as described herein. The Fmoc group is removed using theprocedure described herein, and the resulting resin intermediate 2 isallowed to react with the relevant sulfonyl chloride. Similarly,N-sulfonamides of 10-mer peptide analogs may be prepared starting from aprotected 10-mer peptidyl-resin intermediate, Fmoc removal and reactionof the resulting peptidyl-resin intermediate with the relevant sulfonylchloride.

[0148] (F) General procedure for the synthesis of N-sulfonylureaderivatives of 11-mer peptide analogs.

[0149] The synthesis of N-sulfonylurea derivatives of 11-mer peptideanalogs may be started from the protected 11-mer peptidyl-resinintermediate (1) (0.025 mmol), prepared as described herein. The Fmocgroup is removed using the procedure described herein, and the resultingresin intermediate 2 is allowed to react with the relevant sulfamoylchloride R₄R₅N—SO₂—Cl to yield a sulfonyl urea intermediate (see, forexample, P. Davern et al. J. Chem. Soc., Perkin Trans. 2, 1994 (2),381-387). Similarly, N-sulfonyl urea derivatives of 10-mer peptideanalogs may be prepared starting from a protected 10-mer peptidyl-resinintermediate, Fmoc removal and reaction of the resulting peptidyl-resinintermediate with the relevant sulfamoyl chloride R₄R₅N—SO₂—Cl.

EXAMPLE 3 Synthesis of N-arylalkyl Amides of 10-mer Peptide Analogs

[0150] The synthesis of N-arylalkyl amides of 10-mer peptide analogs wasstarted with a reductive alkylation reaction of a relevantarylalkylamine with an alkoxybenzaldehyde resin resin as in thefollowing example. 2-(3,5-Dimethoxy-4-formylphenoxy)ethoxymethylpolystyrene resin (Novabiochem, 1.12 mmol/gram, 0.025 mmol, 27.3 mg) waswashed with 1% Acetic Acid in DCM (5×3 mL). A solution of2-(2-pentafluorophenyl)ethyl amine (0.125 mmol, 26.4 mg) in DCM (3 mL)was added to the resin. After 5 minutes, solid NaBH(OAc)₃ (0.125 mmol,26.5 mg,) was added and the reaction was vortexed for 16 hours. Theresin was rinsed with DMF (5×3 mL) and DCM (5×3 mL). A solution ofFmoc-[BIP(2-Et)]-OH (0.05 mmol, 25.3 mg) and HOAt(0.05 mmol, 6.81 mg) inNMP(0.5 mL) was added to the resin followed by DIC (0.05 mmol, 7.82 μL).The reaction was vortexed for 16 hrs. The resin was rinsed with NMP(5×3mL). The remaining sequence of the desired 10-mer N-arylalkyl amideanalog was then assembled as described in Example 1.

EXAMPLE 4 Solid Phase Synthesis of 11-mer Peptide Analogs Using anApplied Biosystems Model 433A Peptide Synthesizer

[0151] Following is the general description for the solid phasesynthesis of typical 11-mer peptide analogs, using an upgraded AppliedBiosystems Model 433A peptide synthesizer. The upgraded hardware andsoftware of the synthesizer enabled conductivity monitoring of the Fmocdeprotection step with feedback control of coupling. The protocolsallowed a range of synthesis scale from 0.05 to 1.0 mmol.

[0152] The incorporation of the two non-natural C-terminal amino acidresidues was described earlier in connection with simultaneous synthesisof 11-mer analogs. Such a Fmoc-protected dipeptidyl resin was used inthis ABI synthesis. The Fmoc-protected dipeptidyl-resin (0.1 mmol) wasplaced into a vessel of appropriate size on the instrument, washed 6times with NMP and deprotected using two treatments with 22%piperidine/NMP (2 and 8 min. each). One or two additional monitoreddeprotection steps were performed until the conditions of the monitoringoption were satisfied (<10% difference between the last twoconductivity-based deprotection peaks). The total deprotection time was10-12 min. The deprotected dipeptidyl-resin was washed 6 times with NMPand then coupled with the next amino acid. The procedure is illustratedby the example used in the next step. Thus, Fmoc-Asp(OtBu)-OH wascoupled next using the following method: Fmoc-Asp(OtBu)-OH (1 mmol, 10eq.) was dissolved in 2 mL of NMP and activated by subsequent additionof 0.45 M HBTU/HOBt in DMF (2.2 mL) and 2 M DIEA/NMP (1 mL). Thesolution of the activated Fmoc-protected amino acid was then transferredto the reaction vessel and the coupling was allowed to proceed for 30 to60 min., depending on the feedback from the deprotection steps. Theresin was then washed 6 times with NMP, and subjected to 8 additionaldeprotection/coupling cycles as described above in order to complete theassembly of the desired sequence. The Fmoc-amino acids sequentially usedwere: Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Phe-OH, Fmoc-Thr(tBu)-OH,Fmoc-Gly-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Ala-OH and Fmoc-His(Trt)-OH.Finally, the Fmoc group was removed with 22% piperidine in NMP asdescribed above, and the peptidyl-resin was washed 6 times with NMP andDCM, and dried in vacuo.

[0153] Alternatively, a modified coupling protocol was used in which theFmoc-protected amino acid (1 mmol) was activated by subsequent additionof 0.5 M HOAt in NMP (2 mL) and 1 M DIC/NMP (1 mL), transferred to thereaction vessel and allowed to couple for 1-2 hrs.

Cleavage/Deprotection

[0154] The desired peptide was cleaved/deprotected from its respectivepeptidyl-resin (0.141 g) by treatment with a solution ofTFA/water/tri-isopropylsilane (94:3:3) (2.5 mL) for 2 hrs. The resin wasfiltered off, rinsed with TFA cleavage solution (0.5 mL), and thecombined TFA filtrates were dried in vacuo. The resulting solid wastriturated and washed with diethyl ether, and finally dried, to yield35.6 mg (58%) of crude peptide product as a white solid. This waspurified by preparative HPLC as described herein. The gradient used wasfrom 20% to 75% 0.1% TFA/MeCN in 0.1% TFA/water over 15 min. Thefraction containing a pure product was lyophilized, to yield 7.2 mg (20%recovery) of pure product.

EXAMPLE 5 Synthesis of Biphenylalanine Analogs at Position -10 andPosition -11

[0155] For those analogs wherein position-10 and position-11 residueswere represented by substituted phenylalanine analogs, i.e.biphenylalanine analogs (Bip-analogs), their incorporation into thepeptide chain was carried out in one of two approaches.

Approach A: Solid phase Suzuki condensation

[0156] In approach A, solid phase Suzuki condensation was practiced toprepare the required modified phenylalanine residue in a manner suitablefor carrying out subsequent solid phase peptide synthesis to obtain thetarget peptides. When the amino acid at position-11 in the targetpeptide was represented by a modified phenylalanine residue, it wasprepared as shown in Scheme 3. After removal of the Boc α-amineprotecting group, chain elongation was continued using multiple peptidesynthesis as described in the previous section to obtain the desired11-mer peptides or its derivatives thereof. When the modifiedphenylalanine analog was in position-10 of the target peptides, therequired amino acid was prepared using a suitable dipeptide resin asshown in Scheme 4. The resulting dipeptidyl resin containing therequired modified phenylalanine derivative was then used to carry outthe synthesis of the target 11-mer peptide or its derivatives thereof.When both position-10 and position-11 required novel biphenylalanineresidues, two sequential solid phase Suzuki reactions were carried outas shown in Scheme 5.

[0157] General Procedure for preparation of resin containingbiphenylalanine residue at position-11 (Suzuki couplings).

[0158] Procedure A:

[0159] Polystyrene (1% DVB crosslinked) resins (50 mg, 0.025 mmole)derivatized with an N^(α)-Boc-4-iodophenylalanine residue eitherattached directly via a Knorr linkage (Boc-amino acid-resin) or via anamino acid-Knorr linkage (Boc-dipeptide-resin) were weighed into 13×100mm glass culture tubes with screw caps. Aryl-boronic acids (0.5 mmole)were dissolved in 0.75 ml of 25% by volume diisopropylethylamine inN-methylpyrolidinone and added to the resins followed by 0.05 ml of anN-methylpyrolidinone solution containing 1.0 mg oftetrakis(triphenylphospine)palladium(0) catalyst (ca. 3.5 mole %). Theresulting mixtures were blanketed with a stream of nitrogen and thereaction vessels tightly capped and maintained at 85-90° C. for 17-20hours with periodic shaking. The resins were washed with 5×1 ml ofN-methylpyrolidinone and 5×1 ml of dichloromethane prior to Boc groupcleavage (see General Procedure below).

[0160] Procedure B:

[0161] The reactions were performed as in General Procedure A except adifferent catalyst was employed. The catalyst solution was prepared bydissolving 9.0 mg of palladium(II) acetate and 56 mg of2-(dicyclohexylphosphino)biphenyl in 2.0 ml of N-methylpyrolidinone. For0.025 mmole scale reactions, 0.038 ml (ca. 3 mole %) of catalystsolution was employed.

Procedures for Cleavage of the Boc Group

[0162] Method A: The Boc-protected resins prepared as described inGeneral Procedures A or B were treated with 0.5 ml of reagent solutionconsisting of trimethylsilyl trifluoromethanesulfonate, 2,6-lutidine anddichloromethane (1:1:3 by volume). After 3 such reagent treatments for 1hour each with shaking, the resins were washed with 4×1 ml ofdichloromethane, 3×1 ml of N,N-dimethylformamide, 3×1 ml of 20% MeOH inN,N-dimethylformamide and 4×1 ml dichloromethane prior to transfer tothe automated peptide synthesizer.

[0163] Method B: The Boc-protected resins prepared as described inGeneral Procedures A or B were treated with 1.0 ml of 1N HCl inanhydrous 1,4-dioxane for 1 hour at room temperature with shaking. Theresins were washed with 4×1 ml of dichloromethane, 3×1 ml of 5%diisopropylethylamine in dichloromethane (vol:vol), 3×1 ml ofdichloromethane, and 5×1 ml of N-methylpyrolidinone to provide the freeamino-resins ready for the next acylation (coupling reaction) step.

EXAMPLE 6 General Procedure for Preparation of a Resin Containing aModified Biphenylalanine Residue at Position-10

[0164] The general procedures described above (A or B) for Suzukicoupling were utilized to obtain the required dipeptidyl resincontaining modified Phe at position-10 starting with the amino acid (atposition-11) bound resin as shown in Scheme 4.

EXAMPLE 7 General Procedure for Preparation of Resin Containingbiphenylalanine Residues at Both Positions 10 and 11

[0165] Utilizing the procedures described for position 11 modifiedanalogs (Scheme 1) and carrying out the Suzuki coupling procedure twosuccessive times produced dipeptidyl resins containing modifiedphenylalanine residues at both positions-10 and -11 as illustrated inScheme 5.

[0166] Approach B: Synthesis of Fmoc-biphenylalanine derivatives usingSuzuki Condensation in solution.

[0167] Using this method, exemplified by the synthesis ofFmoc-2-methyl-biphenylalanine, several N-α-Fmoc protectedbiphenylalanine derivatives were prepared. They were utilized for thesolid phase synthesis of 11-mers and other peptide analogs as describedherein.

EXAMPLE 8 Synthesis of Fmoc-2-methyl-biphenylalanine

[0168] The following scheme 6 describes the synthesis ofFmoc-2-methyl-biphenylalanine.

[0169] Boc-L-Tyrosine-O-triflate: To a solution of 37 g (126 mmol ofBoc-tyrosine methyl ester, and 25.4 mL (314 mmol, 2.5 eq.) of pyridinein 114 mL of dry dichloromethane, kept at −15° C. under N₂, was addedslowly 25.4 mL (151 mmol, 1.2 eq.) of triflic anhydride. The solutionwas stirred at −15° C. for 15 min. HPLC analysis indicated that thereaction was complete. The reaction was quenched by addition of 150 mLof water. The layers were separated, and the organic layer washed with2×150 mL of 0.5M NaOH, and 2×150 mL of 15% citric acid solution. Theorganic layer was dried over magnesium sulfate, filtered concentratedand dried in vacuo to give the crude product as a red oil. (Crude yieldvaried between 90% to quantitative).

[0170] Boc-(2-Me) biphenylalanine methyl ester: The above red oil wasdissolved in 70 mL of toluene, and added to a degassed suspensioncontaining 19.0 g (140 mmol, 1.2 eq.) of o-tolyllboronic acid, 24.1 g(175 mmol, 1.5 eq.) of potassium carbonate, and 4.6 g (4.0 mol, 0.034eq.) of tetrakis(triphenylphosphine) palladium (0) in 580 mL of toluenepreheated at 80° C. The mixture was heated at 80° C. under N₂ for 3h,cooled to room temperature, and then filtered through celite. Thereaction mixture was washed with 2×150 mL of 0.5% of NaOH, and 2×150 mLof 15% citric acid solution, dried over magnesium sulfate andconcentrated. The crude mixture thus obtained was purified by silica gelchromatography using ethyl acetate/heptane (1:9) as eluant, [crudemixture was preabsorbed on silica gel (2 g silica gel/g crude mixture),1:35::mixture:silica gel used for the column], yield varied from 50 to80%.

[0171] Boc-(2-Me) biphenylalanine: To a solution of 44.5 g (120 mmol) ofBoc-(2-Me) biphenylalanine methyl ester in 147 mL of methanol and 442 mLof tetrahydrofuran, kept at room temperature, was added 147.4 mL of 1NNaOH (147 mmol, 1.2 eq.). HPLC analysis indicated that the reaction wascomplete after 1h. The reaction mixture was concentrated and partitionedbetween 500 mL of water and 300 mL of ether. The ethereal solution wasdiscarded. Aqueous layer was acidified with 160 mL of 1 N HCl solution,and then extracted with 2×250 mL of ethyl ether. The ethereal solutionswere combined, and dried over magnesium sulfate. After filtration,concentration and drying 41.5 g of product was obtained.

[0172] Fmoc-(2-Me) biphenylalanine: To a solution of 41.5 g (117 mmol)of Boc-(2-Me) biphenylalanine in 1 L of dichloromethane, kept at roomtemperature, was bubbled in gaseous HCl. A white solid started toprecipitate in approximately 5 min. HPLC taken after 2 hours showed thatthe reaction was complete. The mixture was concentrated. The residue wasredissolved in 600 mL of tetrahydrofuran and 150 mL of water, and solidNaHCO₃ was added slowly until the pH of the mixture was basic (a whitesolid precipitated out), followed by addition of 38.9 g (115 mmol, 1eq.) of Fmoc-Osu. The mixture was then stirred at room temperature. Ahomogeneous biphasic solution was obtained within 1 h. The stirring wascontinued at room temperature under N₂ overnight. The layers wereseparated. The tetrahydrofuran layer was acidified with 58 mL 2N HCl,and then diluted with 400 mL of ethyl acetate. The layers wereseparated, and the organic layer washed with 2×100 mL of water, driedover magnesium sulfate, and concentrated. The crude product was purifiedusing silica gel column chromatography using dichoromethane as eluantuntil most of the impurities had been removed. The solvent was thenchanged to 25% ethyl acetate in heptane containing 1% acetic acid,[approximately 23 g silica gel/g crude mixture used for the column]. Theyield was >90% for the three steps.

EXAMPLE 9 General Synthesis of Various Fmoc-biphenylalanine Derivatives

[0173] Synthesis of various biphenyl alanine derivatives were carriedout using the above described procedure, starting with the commerciallyavailable phenol derivative (e.g. Boc-Tyrosine methyl ester) to preparethe triflate and using the appropriate boronic acid to prepare thebiphenylalanine analogs. When a required boronic acid was not availablefrom commercial sources the synthesis of this intermediate was carriedout as exemplified in the following example.

[0174] 2-Ethylphenyl boronic acid: To a solution of 25 g (135 mmol) of1-bromo-2-ethylbenzene in 280 mL of dry tetrahydrofuran, kept at −78° C.in an oven-dried 3 neck flask, was added slowly (keeping the temperaturebelow −68° C.) 67.5 mL of 2.5N n-Butyl lithium in hexanes solution (169mmol, 1.25 eq.). The reaction was stirred for an additional 1h, and then69 mL (405 mmol, 3 eq.) of triethylborate was added slowly, keeping thetemperature below −68° C. The reaction was stirred for an additional 40minutes and then the dry ice bath was removed, the reaction was allowedto warm up to room temperature, and then was poured into 300 mL of icecold saturated ammonium chloride solution. 200 mL of ice cold ethylacetate was added, and the mixture stirred for another 30 min. Thelayers were separated. The organic layer was washed with water, andbrine. It was then dried over magnesium sulfate, and concentrated togive 19 g (92% yield) of product. The boronic acid was used withoutpurification in the next step.

EXAMPLE 10 Synthesis of Fmoc-protected Biphenylalanine Analogs withSubstitution in the Internal Phenyl Ring

[0175] Synthesis of the Fmoc-protected biphenylalanine analogs withsubstitution in the phenyl ring directly attached to the β-carbon(internal ring) of the amino acid moiety was carried as depicted in thefollowing scheme 7.

[0176] As a general method, initially a suitably protected tyrosinederivative was prepared by reaction of Boc-β-iodo alanine with therequired 4-iodophenol derivative using a zinc mediated condensation. Theproduct from this reaction was subjected to Suzuki condensation reactionas described herein, to afford the required Fmoc-protectedbiphenylalanine analogs with substitution in the phenyl ring directlyattached to the β-carbon (internal ring) of the amino acid moiety.Synthesis of a specific example, Fmoc-2′-methyl-2-methyl-biphenylalnineis given below.

[0177] Boc-2′-Methyl-Tyrosine benzyl ether methyl ester: 2.2 g (33 mmol)of oven-dried zinc dust was placed in an oven dried flask undernitrogen. 5.2 mL of dry tetrahydrofuran, and 140 μL (1.6 mmol) of1,2-dibromoethane were added, and the mixture warmed briefly with a heatgun until the solvent began to boil, and then stirred vigorously for afew minutes. This procedure was repeated five times, and then thereaction mixture was cooled to 35° C. 40 μL (0.32 mmol) ofchlorotrimethylsilane was added, and the mixture stirred vigorously at35° C. for 30 min. A solution of 3 mL of 1.04 g (3.17 mmol) ofBoc-iodoalanine methyl ester in 1:1 tetrahydrofuran: dimethylacetamidewas added slowly, and the reaction mixture stirred at 35° C. for 30 min.A solution of 3 mL of 1:1 tetrahydrofuran:dimethylacetamide containing819 mg (2.5 mmol) of 4-iodo-2-methyl-1-benzyloxybenzene was addedslowly, followed by 338 mg (1.11 mmol) of tri-o-tolylphosphine, and 288mg (0.31 mmol) of Pd₂(dba)₃. The reaction mixture was degassed, and thenstirred at 60° C. for 4 h. The reaction mixture was cooled to roomtemperature, diluted with ethyl acetate, and filtered through celite.The filtrate was washed with 2×25 mL of 1N HCl, dried over magnesiumsulfate, filtered and concentrated. The product was purified by silicagel chromatography (72% yield).

[0178] Boc-2′-Methyl-Tyrosine methyl ester: A suspension of 7.5 g (18.7mmol) of the above compound (Boc-2′-methyl-tyrosine benzyl ether methylester) in 30 mL of tetrahydrofuran, and 2.25 g 10% Degussa type 10%palladium on carbon was stirred under hydrogen atmosphere at roomtemperature and atmospheric presssure for 2 days. The reaction mixturewas then filtered through celite, and concentrated. The product waspurified by silica gel chromatography (74% yield).

[0179] Fmoc-2′-methyl-2-methyl-biphenyl alanine: This compound wasprepared using the Suzuki Condensation procedure described herein, usingBoc-2′-Methyl-Tyrosine methyl ester as the starting material. Theproduct obtained in the above Suzuki condensation reaction, afterremoval of the Boc-group and reprotection with Fmoc-group usingconditions described herein afforded the desired product.

EXAMPLE 11 Utilizing the Synthetic Methods Described Herein theFollowing GLP-1 Mimic Peptides Were Prepared.

[0180] TABLE I [The peptide sequences listed below contain a free aminogroup at the N-terminus and a carboxamide at the C-terminus] Com- pound# Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 Xaa7 Xaa8 Xaa9 Y Z 1 H A E G T F T S DBip Phe(4-NO2) 2 H A E G T F T S D Bip 2-Nal 3 H A E G T F T S D Bip Bip4 H A E G T F T S D Bip Phe(penta-Fluoro) 5 H A E G T F T S D BipPhe(4-Me) 6 H A E G T F T S D 2-Nal Bip 7 H A E G T F T S D Bip F 8 H AE G T F T S D Bip Y 9 H A E G T F T S D 2-Nal Phe(penta-Fluoro) 10 H A EG T F T S D Bip Phe(4-Iodo) 11 H A E G T F T S D Bip(2-Me) Bip(4-OMe) 12H A E G T F T S D Bip(2-Me) Bip(3,4- Methylenedioxy) 13 H A E G T F T SD Bip(2-Me) 4-(1-Naphthyl)-Phe 14 H A E G T F T S D Bip(2-Me) Bip(4-Me)15 H A E G T F T S D Bip(2-Me) Bip(3-Me) 16 H A E G T F T S DBip(2,4-di—OMe) Bip(2-Me) 17 H A E G T F T S D Bip(2-Me,4-OMe) Bip(2-Me)18 H A D G T F T S D Bip(2-Me) Bip(2-Me) 19 H A E G Nle F T S DBip(2-Me) Bip(2-Me) 20 H A E G T Phe(penta- T S D Bip(2-Me) Bip(2-Me)Fluoro) 21 H A H G T Phe(penta- T S D Bip(2-Me) Bip(2-Me) Fluoro) 22 H AD G Nle F T S D Bip(2-Me) Bip(2-Me) 23 H A E G Nle Phe(penta- T S DBip(2-Me) Bip(2-Me) Fluoro) 24 H A E G Nle F T H D Bip(2-Me) Bip(2-Me)25 H ala D G Nle F T S D Bip(2-Me) Bip(2-Me) 26 H ala D G T Phe(penta- TS D Bip(2-Me) Bip(2-Me) Fluoro) 27 H A H G Nle Phe(penta- T S DBip(2-Me) Bip(2-Me) Fluoro) 28 H A H G T Phe(penta- T H D Bip(2-Me)Bip(2-Me) Fluoro) 29 H A D G T Phe(penta- T H D Bip(2-Me) Bip(2-Me)Fluoro) 30 H A D G Nle F T H D Bip(2-Me) Bip(2-Me) 31 H ala D G NlePhe(penta- T S D Bip(2-Me) Bip(2-Me) Fluoro) 32 H A E G T F T S DBip(2-Et) Bip 33 H A E G Nle Phe(penta- T H D Bip(2-Me) Bip(2-Me)Fluoro) 34 H A E G T F T S D Bip(2-OEt) Bip(2-Me) 35 H A E G T F T S DBip(2-Propyl) Bip(2-Me) 36 H A E G T F T S D Bip(2-Propyl,4- Bip(2-Me)OMe) 37 H A E G T F T S D Bip(2- Bip Trifluoromethyl) 38 H A E G T F T SD Bip(2-Chloro) Bip 39 H A E G T F T S D Bip(4-Fluoro) Bip 40 H A E G TF T S D Bip(4- Bip Trifluoromethyl) 41 H A E G T F T S D4-(1-Naphthyl)-Phe Bip 42 H A E G T F T S D 4-(3-thiophene)-Phe Bip 43 HA E G T F T S D 4-(3-Quinoline)-Phe Bip 44 H A E G T F T S D Bip(2-Me)Phe(penta-Fluoro) 45 H A E G T F T S D Bip(2-OMe) Phe(penta-Fluoro) 46 HA E G T F T S D Bip(2- Phe(penta-Fluoro) Trifluoromethyl) 47 H A E G T FT S D Bip(2- Phe(penta-Fluoro) Trifluoromethyl) 48 H A E G T F T S DBip(2-Chloro) Phe(penta-Fluoro) 49 H A E G T F T S D Bip(2-Fluoro)Phe(penta-Fluoro) 50 H A E G T F T S D Bip(4-OMe) Phe(penta-Fluoro) 51 HA E G T F T S D Bip(3,4- Phe(penta-Fluoro) Methylenedioxy) 52 H A E G TF T S D Bip(2-Me) 2-Nal 53 H A E G T F T S D Bip(2-OMe) 2-Nal 54 H A E GT F T S D Bip(2- 2-Nal Trifluoromethyl) 55 H A E G T F T S DBip(2-Chloro) 2-Nal 56 H A E G T F T S D Bip(2-Fluoro) 2-Nal 57 H A E GT F T S D Bip(4-Me) 2-Nal 58 H A E G T F T S D Bip(4-OMe) 2-Nal 59 H A EG T F T S D Bip(3,4- 2-Nal Methylenedioxy) 60 H A E G T F T S D4-(1-Naphthyl)-Phe 2-Nal 61 H A E G T F T S D 4-(3-thiophene)-Phe 2-Nal62 H A E G T F T S D Bip(2-Me) Phe(4-Me) 63 H A E G T F T S D Bip(2-Phe(4-Me) Trifluoromethyl) 64 H A E G T F T S D Bip(2-Chloro) Phe(4-Me)65 H A E G T F T S D Bip(2-Fluoro) Phe(4-Me) 66 H A E G T F T S DBip(4-Chloro) Phe(4-Me) 67 H A E G T F T S D Bip(4-Me) Phe(4-Me) 68 H AE G T F T S D Bip(4-Fluoro) Phe(4-Me) 69 H A E G T F T S D Bip(4-OMe)Phe(4-Me) 70 H A E G T F T S D Bip(3,4- Phe(4-Me) Methylenedioxy) 71 H AE G T F T S D 4-(1-Naphthyl)-Phe Phe(4-Me) 72 H A E G T F T S DBip(3-Phenyl) Phe(4-Me) 73 H A E G T F T S D Bip(2-Me) Bip(2-Fluoro) 74H A E G T F T S D Bip(2-Me) Bip(4-Phenyl) 75 H A E G T F T S D Bip(2-Me)Bip(3-OMe) 76 H A E G T F T S D Bip(2-Me) 4-(3-Pyridyl)-Phe 77 H A E G TF T S D Phe(penta-Fluoro) Bip(4-OMe) 78 H A E G T F T S D Bip(2-Me)Bip(3-Acetamido) 79 H A E G T F T S D Bip(2-Me) Bip(4-Isopropyl) 80 H AE G T F T S D Bip 4-(1-Naphthyl)-Phe 81 H A E G T F T S D Bip4-(3-Pyridyl)-Phe 82 H A E G T F T S D Phe(penta-Fluoro) Bip(2-Me) 83 HA E G T F T S D 2-Nal Bip(2-Me) 84 H A E G T F T S D Phe(4-Iodo)Bip(2-Me) 85 H A E G T F T S D Phe(3,4-di-Chloro) Bip(2-Me) 86 H A E G TF T S D Tyr(Bzl) Bip(2-Me) 87 H A E G T F T S D homoPhe Bip(2-Me) 88 H AE G T F T S D Bip(2,4-di—OMe) Bip 89 H A E G T F T S D 4-(4-(3,5- Bipdimethylisoxazole))- Phe 90 H A E G T F T S D Bip(2-Me,4-OMe) Bip 91 H AE G T F T S D Bip(2,6-di—Me) Bip 92 H A E G T F T S D Bip(2,4-di—Me) Bip93 H A E G T F T S D Bip(2,3-di—Me) Bip 94 H A E G T F T S D Bip(4- BipTrifluoromethoxy) 95 H A E G T F T S D Bip(4-Et) Bip 96 H A E G T F T SD 4-(2-Naphthyl)-Phe Bip 97 H A E G T F T S D 4-(4-Dibenzofuran)- BipPhe 98 H A E G T F T S D Bip(2,6-di—OMe) Bip(2-Me) 99 H A E G T F T S D4-(2,4- Bip(2-Me) dimethoxy- pyrimidine)-Phe 100 H A E G T F T S DBip(2,4,6- Bip(2-Me) Trimethyl) 101 H A E G T F T S D 4-(4-(3,5-Bip(2-Me) dimethylisoxazole))- Phe 102 H A E G T F T S DBip(2,4-di-Chloro) Bip(2-Me) 103 H A E G T F T S D Bip(2,6-di—Me)Bip(2-Me) 104 H A E G T F T S D Bip(2,4-di—Me) Bip(2-Me) 105 H A E G T FT S D Bip(2,3-di—Me) Bip(2-Me) 106 H A E G T F T S D Bip(4-Et) Bip(2-Me)107 H A E G T F T S D Bip(4-SMe) Bip(2-Me) 108 H A E G T F T S DBip(4-OEt) Bip(2-Me) 109 H A E G T F T S D 4-(2-Naphthyl)-Phe Bip(2-Me)110 H A E G T F T S D 4-(2- Bip(2-Me) Benzo(b)thiophene)- Phe 111 H A EG T F T S D 4-(2- Bip(2-Me) Benzo(b)furan)-Phe 112 H A E G T F T S D4-(4-Dibenzofuran)- Bip(2-Me) Phe 113 H A E G T F T S D4-(4-Phenoxathiin)- Bip(2-Me) Phe 114 H A E G T F T S D Bip(2-Me)Bip(4-Et) 115 H A E G T F T S D Bip(2-Me) Bip(4-SMe) 116 H A E G T F T SD Bip(2-Me) Bip(2,4-di—Me) 117 H A E G T F T S D Bip(2-Me)Bip(2-Me,4-OMe) 118 H A E G T F T S D Bip(2-Me) Bip(2,3-di—Me) 119 H A EG T F T S D Bip(2-Me) 4-(2-naphthyl)-Phe 120 H A E G T F T S D Bip(2-Me)Bip(2-OEt) 121 H A E G T F T S D Bip(2-Me) Bip(2-Et,4-OMe) 122 H A E G TF T S D Bip(2-Et) Bip(3-Et) 123 H A E G T F T S D Bip(2-Et)Bip(3-Propyl) 124 H A E G T F T S D Bip(2-Et) Bip(3-Phenyl) 125 H A E GT F T S D Bip(2-Et) Bip(3-OEt) 126 H A E G T F T S D Bip(2-Et) Bip(4-Et)127 H A E G T F T S D Bip(2-Et) Bip(4-SMe) 128 H A E G T F T S DBip(2-Et) Bip(4-OCF3) 129 H A E G T F T S D Bip(2-Et) Bip(4-OEt) 130 H AE G T F T S D Bip(2-Et) Bip(2-Me,4-OMe) 131 H A E G T F T S D Bip(2-Et)Bip(2,6-di—Me) 132 H A E G T F T S D Bip(2-Et) Bip(2,4,6-tri—Me) 133 H AE G T F T S D Bip(2-Et) Bip(2-Phenyl) 134 H A E G T F T S D Bip(2-Et)Bip(2-Isopropyl) 135 H A E G T F T S D Bip(2-Et) 4-(2-naphthyl)-Phe 136H A E G T F T S D Bip(2-Et) Bip(2,5-di—OMe) 137 H A E G T F T S DBip(2-Et) Bip(2-OEt) 138 H A E G T F T S D Bip(2-Et) Bip(3,4-di—OMe) 139H A E G T F T S D Bip(2-Et) Bip(2-Et,4-OMe) 140 H ala E G Nle Phe(penta-T S D Bip(2-Me) Bip(2-Me) Fluoro) 141 H A H G T F T H D Bip(2-Me)Bip(2-Me) 142 H A H G T F T S D Bip(2-Me) Bip(2-Me) 143 H A E G T F T SD Bip Phe(4- Trifluoromethyl) 144 H Aib E G Nle Phe(penta- T S DBip(2-Et) Bip(2-Me) Fluoro) 145 H Aib D G T F T S D Bip(2-Et) Bip(2-Me)146 H Aib D G Nle F T H D Bip(2-Et) Bip(2-Me) 147 H Aib H G T Phe(penta-T H D Bip(2-Et) Bip(2-Me) Fluoro) 148 H Aib D G Nle F T S D Bip(2-Et)Bip(2-Me) 149 H Aib H G T F T H D Bip(2-Et) Bip(2-Me) 150 H ala asp GNle Phe(penta- T S D Bip(2-Me) Bip(2-Me) Fluoro) 151 H A D G Nle F T H DBip(2-Et) Bip(2-Me) 152 H ala D G Nle Phe(penta- T H D Bip(2-Et)Bip(2-Me) Fluoro) 153 H A D G T (L)-Phe(2,4-di- T S D Bip(2-Me)Bip(2-Me) Fluoro) 154 H Aib asp G Nle Phe(penta- T S D Bip(2-Me)Bip(2-Me) Fluoro) 155 H A D G T (D)-Phe(2,4-di- T S D Bip(2-Me)Bip(2-Me) Fluoro) 156 H Aib D G Nle F T H D Bip(2-Me) Bip(2-Me) 157 HAib D G Nle F T S D Bip(2-Me) Bip(2-Me) 158 H Aib D G T F T S DBip(2-Me) Bip(2-Me) 159 H Aib D G T Phe(penta- T S D Bip(2-Me) Bip(2-Me)Fluoro) 160 H Aib E G Nle F T S D Bip(2-Me) Bip(2-Me) 161 H Aib E G NlePhe(penta- T H D Bip(2-Me) Bip(2-Me) Fluoro) 162 H Aib E G NlePhe(penta- T S D Bip(2-Me) Bip(2-Me) Fluoro) 163 H Aib E G T Phe(penta-T H D Bip(2-Me) Bip(2-Me) Fluoro) 164 H Aib E G T Phe(penta- T S DBip(2-Me) Bip(2-Me) Fluoro) 165 H Aib H G T F T H D Bip(2-Me) Bip(2-Me)166 H Aib H G T F T S D Bip(2-Me) Bip(2-Me) 167 H Aib H G T Phe(penta- TH D Bip(2-Me) Bip(2-Me) Fluoro) 168 his Aib D G Nle Phe(penta- T S DBip(2-Me) Bip(2-Me) Fluoro) 169 H ala D G Nle Phe(penta- T S D Bip(2-Et)Bip(2-Me) Fluoro) 170 H Aib D G Nle Phe(penta- T S D Bip(2-Et) Bip(2-Me)Fluoro) 171 H Aib D G Nle Phe(penta- T S D Bip(2-Me) Bip(2-Et) Fluoro)172 H Aib D G Nle Phe(penta- T S D Phe(penta-Fluoro) Bip(2-Me) Fluoro)173 H ala D G T Phe(penta- T S D Bip(2-Et) Bip(2-Me) Fluoro) 174 H Aib EG T Phe(penta- T S D Bip(2-Et) Bip(2-Me) Fluoro) 175 H A D G T(L)-Phe(2,5-di—F) T S D Bip(2-Me) Bip(2-Me) 176 H A Dpr G T Phe(penta- TS D Bip(2-Et) Bip(2-Me) Fluoro) 177 H Aib Dpr G T Phe(penta- T S DBip(2-Et) Bip(2-Me) Fluoro) 178 H ala Dpr G Nle Phe(penta- T S DBip(2-Et,2′-Me) Bip(2-Me) Fluoro) 179 H A Dpr G T Phe(penta- T S DBip(2-Et,2′-Me) Bip(2-Me) Fluoro) 180 H A Dpr G T F T S DBip(2-Et,2′-Me) Bip(2-Me) 181 H IVa E G T F T S D Bip(2-Me) Bip(2-Me)182 H A E G homo- F T S D Bip(2-Me) Bip(2-Me) Leu 183 H A E G T homoLeuT S D Bip(2-Me) Bip(2-Me) 184 H A E G T F T S D 2-(9,10- Bip(2-Me)Dihydro- phenanthrenyl)- Ala 185 H A E G T F T S D Bip(2-Et) 2-(9,10-Dihydro- phenanthrenyl)- Ala 186 H A E G T F T S D Bip(2-Et) 2-(9,10-Dihydro- phenanthrenyl)- Ala 187 H A E G T F T S D 2-(9,10- 2-(9,10-Dihydro- Dihydro- phenanthrenyl)- phenanthrenyl)- Ala Ala 188 H A E G TF T S D 2-(9,10- 2-(9,10- Dihydro- Dihydro- phenanthrenyl)-phenanthrenyl)- Ala Ala 189 H A E G T F T S D 2-FluorenylAla 2-(9,10-Dihydro- phenanthrenyl)- Ala 190 H A E G T F T S D 2-(9,10-2-FluorenylAla Dihydro- phenanthrenyl)- Ala 191 H A E G T F T S D2-(9,10- 2-FluorenylAla Dihydro- phenanthrenyl)- Ala 192 H A E G T F T SD Bip(2-Et,2′-Et) Bip 193 H A E G T F T S D Bip(2-Et,2′-Et) Bip(2-Me)194 H ala D G Nle Phe(penta- T S D Bip(2-Et,4-OMe) Bip(2-Me) Fluoro) 195H A E G T F T S D Bip(2-Propyl,2′-Me) Bip 196 H A D G T L-α-Me—Phe T S DBip Bip(2-Et) 197 H A D G T L-α-Me—Phe T S D Bip(2-Et) Bip(2-Et) 198 H AD G T L-α-Me—Phe T S D Bip(2-Me) Bip(2-Et) 199 H ala E G T L-α-Me—Phe TS D Bip(2-Et) Bip(2-Me) 200 H A D G T L-α-Me—Phe T S D Bip Bip 201 H alaasp G Nle L-α-Me—Phe T S D Bip(2-Me) Bip(2-Me) 202 H ala D G nleL-α-Me—Phe T S D Bip(2-Me) Bip(2-Me) 203 H Aib D G nle L-α-Me—Phe T S DBip(2-Me) Bip(2-Me) 204 H Aib D G Nle L-α-Me—Phe thr S D Bip(2-Me)Bip(2-Me) 205 H Aib D G Nle L-α-Me—Phe T ser D Bip(2-Me) Bip(2-Me) 206 HAib D G Nle L-α-Me—Phe T S D Bip(2-Me) Bip 207 H G E G T F T S DBip(2-Me) Bip(2-Me) 208 H A E G T F T S D Bip(2-Et,4-OMe) Bip(2,4-di—Me)209 H A E G T F T S D Bip(2-Et,4-OMe) Bip(4-OMe) 210 H A E G T F T S DBip(2-Et,4-OMe) Bip(3-Me) 211 H A E G T F T S D Bip(2-CH2OH,4- Bip(2-Me)OMe) 212 H A E G T F T S D Bip(2-Me) Bip(2-Propyl,2′- Me) 213 H A E G TF T S D Bip(2-Et,4-OMe) Bip(2,3,4,5-tetra- Me) 214 H A E G T F T S DBip(2-Et) Bip(2,2′-di—Me) 215 H A D G T Phe(2-OMe) T S D Bip(2-Me)Bip(2-Me) 216 H A D G T Phe(2-Hydroxy) T S D Bip(2-Me) Bip(2-Me) 217 H AD G T Phe(2-lodo) T S D Bip(2-Me) Bip(2-Me) 218 H A D G T Phe(3-OMe) T SD Bip(2-Me) Bip(2-Me) 219 H A D G T Tyr(3-lodo) T S D Bip(2-Me)Bip(2-Me) 220 H A D G T Tyr(3-NO2) T S D Bip(2-Me) Bip(2-Me) 221 H A D GT (L)-Phe(2,3-di- T S D Bip(2-Me) Bip(2-Me) Fluoro) 222 H A D G TTyr(2,6-di—Me) T S D Bip(2-Me) Bip(2-Me) 223 H A D G T 2-ThienylAla T SD Bip(2-Me) Bip(2-Me) 224 H A D G T (D)-Phe(2,3-di- T S D Bip(2-Me)Bip(2-Me) Fluoro) 225 H A E G T F T S D Bip(2-Et,2′-Me) Bip(2-Et) 226 Hala D G Nle F T S D Bip(2-Et,2′-Me) Bip(2-Me) 227 H Acc3 D G NlePhe(penta- T S D Bip(2-Me) Bip(2-Me) Fluoro) 228 H Acc3 D G Nle F T H DBip(2-Me) Bip(2-Me) 229 H Acc3 D G T Phe(penta- T H D Bip(2-Me)Bip(2-Me) Fluoro) 230 H Acc3 D G Nle Phe(penta- T H D Bip(2-Me)Bip(2-Me) Fluoro) 231 H A D G T Phe(2- T S D Bip(2-Me) Bip(2-Me)Trifluoromethyl) 232 H A D G T Phe(2,4-di- T S D Bip(2-Me) Bip(2-Me)Chloro) 233 H 2-Abu E G T F T S D Bip(2-Me) Bip(2-Me) 234 his A asp GNle Phe(penta- T S D Bip(2-Me) Bip(2-Me) Fluoro) 235 H A E G NlePhe(penta- T H D Bip(2-Et) Bip(2-Me) Fluoro) 236 H Aib D G T Phe(penta-T S D Bip(2-Et) Bip(2-Me) Fluoro) 237 H Aib E G Nle Phe(penta- T H DBip(2-Et) Bip(2-Me) Fluoro) 238 H A E G T Phe(2-Me) T S D Bip(2-Me)Bip(2-Me) 239 H A E G T F T S D Bip(2-Et) Bip(2-Et) 240 H A E G T F T SD Bip(2-Et,4-OMe) Bip 241 H A E G T Phe(2-Chloro) T S D Bip(2-Me)Bip(2-Me) 242 H A E G T F T S D Bip(2-Et,2′-Me) Bip(2,2′-di—Me) 243 H Aγ- G T F T S D Bip(2-Me) Bip(2-Me) carboxy- Glu 244 H A C G T F T S DBip(2-Me) Bip(2-Me) 245 H ala E G Nle L-α-Me—Phe T S D Bip(2-Et)Bip(2-Me) 246 H L-4- E G T F T S D Bip Bip ThioPro 247 H A E G T F T S DBip Bip(2,2′-di—Me) 248 H A E G T F T S D Bip(2-Me) Bip(2,2′-di—Me) 249H A E G T F T S D Bip(2′-Me) Bip(2-Me) 250 H A E G T F T S D BipBip(2′-Me) 251 H A E G T F T S D Bip(2-Me) Bip(2′-Me) 252 H A E G T F TS D Bip(2′-Me) Bip 253 H Aib E G Nle Phe(penta- T S D bip(2′-Me)Bip(2-Me) Fluoro) 254 H A E G T F T S D Bip(2′-Me) Bip(2,2′-di—Me) 255 HA E G T F T S D Bip(2′-Me) Bip(2′-Me) 256 H A E G T F T S DBip(2,2′-di—Me) Bip 257 H A E G T F T S D Bip(2,2′-di—Me) Bip(2-Me) 258H A E G T F T S D Bip(2,2′-di—Me) Bip(2-Et) 259 H A E G T F T S DBip(2,2′-di—Me) Bip(2,2′-di—Me) 260 H A E G T F T S D Bip(2-Me)Phe(4-n-Butyl) 261 H A E G T F T S D Bip(2-Me) Phe(3-Phenyl) 262 H A E GT F T S D Bip(2-Me) Phe(4-Cyclohexyl) 263 H A E G T F T S D Bip(2-Me)Phe(4-Phenoxy) 264 H A E G T F T S D Phe(4-n-Butyl) Bip(2-Me) 265 H A EG T F T S D Phe(4-Cyclohexyl) Bip(2-Me) 266 H A E G T F T S DPhe(4-Phenoxy) Bip(2-Me) 267 H A D G T Phe(3-Fluoro) T S D Bip(2-Me)Bip(2-Me) 268 H A D G T Phe(4-Fluoro) T S D Bip(2-Me) Bip(2-Me) 269 H AD G T Phe(3,4-di- T S D Bip(2-Me) Bip(2-Me) Fluoro) 270 H A D G TPhe(3,5-di- T S D Bip(2-Me) Bip(2-Me) Fluoro) 271 H A D G TPhe(3,4,5-tri- T S D Bip(2-Me) Bip(2-Me) Fluoro) 272 H ala D G Nle F T HD Bip(2-Me) Bip(2-Me) 273 H ala D G T Phe(penta- T H D Bip(2-Me)Bip(2-Me) Fluoro) 274 H ala E G Nle Phe(penta- T H D Bip(2-Me) Bip(2-Me)Fluoro) 275 H A H G Nle Phe(penta- T H D Bip(2-Me) Bip(2-Me) Fluoro) 276H A D G Nle Phe(penta- T S D Bip(2,4-di—OMe) Bip(2-Me) Fluoro) 277 H A EG T F T S D Bip(2-Me,4-OMe) Bip(3,4- Methylenedioxy) 278 H A E G T F T SD Bip(2-Et) Bip(3,4- Methylenedioxy) 279 H A D G T F T S DBip(2,4-di—OMe) 4-(1-Naphthyl)-Phe 280 H A E G T F T S D Bip(2-Me,4-OMe)4-(1-Naphthyl)-Phe 281 H A D G T F T S D Bip(2,4-di—OMe) Bip(4-OMe) 282H A E G T F T S D Bip(2-Me,4-OMe) Bip(4-OMe) 283 H A E G T F T S DBip(2,4-di—OMe) Bip(4-Me) 284 H A E G T F T S D Bip(2-Me,4-OMe)Bip(4-Me) 285 H A D G T F T S D Bip(2,4-di—OMe) Bip(2,4-di—OMe) 286 H AE G T F T S D Bip(2-Me,4-OMe) Bip(2-Me,4-OMe) 287 H A D G T F T S DBip(2,4-di—Me) Bip(2,4-di—Me) 288 H A E G T F T S D Bip(2,4-di—OMe)Bip(3-Me) 289 H A E G T F T S D Bip(2-Me,4-OMe) Bip(3-Me) 290 H A 4- G TF T S D Bip(2-Me) Bip(2-Me) Thiazoyl Ala 291 H ala D G Nle Phe(penta- TH D Bip(2-Me) Bip(2-Me) Fluoro) 292 H A E G T F T S D Bip(2-Et,4,5-Bip(2-Me) Methylenedioxy) 293 H N—Me— E G Nle Phe(penta- T H D Bip(2-Et)Bip(2-Me) Ala Fluoro) 294 H N—Me— D G Nle Phe(penta- T S D Bip(2-Me)Bip(2-Me) Ala Fluoro) 295 H N—Me— D G T Phe(penta- T S D Bip(2-Me)Bip(2-Me) Ala Fluoro) 296 H N—Me— E G Nle Phe(penta- T H D Bip(2-Me)Bip(2-Me) Ala Fluoro) 297 H N—Me— E G T Phe(penta- T S D Bip(2-Me)Bip(2-Me) Ala Fluoro) 298 H Sarcosyl E G T F T S D Bip(2-Me) Bip(2-Me)299 H A E G T F T S D Bip(3-CH2NH2) Bip(2-Me) 300 H A E G T F T S DBip(2-CH2NH2) Bip(2-Me) 301 H A E G T F T S D Bip(4-CH2NH2) Bip(2-Me)302 H A E G T F T S D Bip(3-CH2— Bip(2-Me) COOH) 303 H A E G T F T S DBip(2-Me) Bip(2′-CH2— COOH) 304 H A E G T F T S D Bip(2-Me)(D,L)-Bip(2-CH2— COOH 305 H A E G T F T S D Bip(2-Me) Bip(4-CH2— COOH)306 H A E G T F T S D Bip(2-Me) Bip(3-CH2— COOH) 307 H A E G T F T S DBip(2-Me) Bip(3-CH2NH2) 308 H A E G T F T S D Bip(2-Me) Bip(4-CH2NH2)309 H A E G T F T S D Bip(2-Me) Bip(2-CH2NH2) 310 H A E G T F T S DPhe[4-(1-propargyl)] Bip(2-Me) 311 H A E G T F T S D Phe[4-(1-propenyl)]Bip(2-Me) 312 H A asp G T L-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) 313 H A DG thr L-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) 314 H A D G T L-α-Me—Phe T Sasp Bip(2-Et) Bip(2-Me) 315 H A D G T L-α-Me—Phe T S D bip(2-Et)Bip(2-Me) 316 H ala asp G T L-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) 317 HAib D G T L-α-Me—Phe thr S D Bip(2-Et) Bip(2-Me) 318 H Aib D G TL-α-Me—Phe T S asp Bip(2-Et) Bip(2-Me) 319 H ala D G Nle Phe(penta- T SD bip(2-Me) Bip(2-Me) Fluoro) 320 H ala D G Nle Phe(penta- T S Dbip(2-Et) Bip(2-Me) Fluoro) 321 H ala D G Nle Phe(penta- T S D Bip(2-Me)bip(2-Me) Fluoro) 322 H ala D G Nle Phe(penta- T S D Bip(2-Me) bip(2-Et)Fluoro) 323 H Aib D G Nle Phe(penta- T S D bip(2-Me) Bip(2-Me) Fluoro)324 H Aib D G Nle Phe(penta- T S D bip(2-Et) Bip(2-Me) Fluoro) 325 H AibD G Nle Phe(penta- T S D Bip(2-Me) bip(2-Me) Fluoro) 326 H Aib D G NlePhe(penta- T S D Bip(2-Me) bip(2-Et) Fluoro) 327 H A E G T F T S DBip(2-Me) (D,L)-α-Me—Bip 328 H A E G T F T S D Bip (D,L)-α-Me—Bip 329 HA D G allo— L-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) Thr 330 H A D G TL-α-Me—Phe allo— S D Bip(2-Et) Bip(2-Me) Thr 331 H A D G T L-α-Me—Phe ThSer D Bip(2-Et) Bip(2-Me) 332 H A D G T L-α-Me—Phe T T D Bip(2-Et)Bip(2-Me) 333 H A D G T L-α-Me—Phe T S E Bip(2-Et) Bip(2-Me) 334 H A E GNle F T S D Bip(2-Et) Bip(2-Me) 335 H A asp G T L-α-Me—Phe T S DBip(2-Et) Bip(2-Me) 336 H Aib D G thr L-α-Me—Phe T S D Bip(2-Et)Bip(2-Me) 337 H Aib D G T L-α-Me—Phe thr S D Bip(2-Et) Bip(2-Me) 338 HAib D G T L-α-Me—Phe T S asp Bip(2-Et) Bip(2-Me) 339 H A D G TL-α-Me—Phe T S D Bip(2-Et)-NH-[2- (penta-Fluoro- phenyl)ethyl] 340 H A DG Nle L-α-Me—Phe T S D Bip(2-Et)-NH-[2- (penta-Fluoro- phenyl)ethyl] 341H Aib E G T L-α-Me—Phe T S D Bip(2-Et)-NH-[2- (penta-Fluoro-phenyl)ethyl] 342 H Aib D G Nle L-α-Me—Phe T S D Bip(2-Et)-NH-[2-(penta-Fluoro- phenyl)ethyl] 343 H Aib asp G T L-α-Me—Phe T S DBip(2-Et) Bip(2-Me) 344 H ala E G T L-α-Me—Phe T S D Bip(2-Et) Bip(2-Me)345 H ala E G T L—Phe(2,6-di- T S D Bip(2-Et) Bip(2-Me) Fluoro) 346 HN—Me— E G T L-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) Ala 347 H A N—Me— G TL-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) Glu 348 H A E N—Me— T L-α-Me—Phe TS D Bip(2-Et) Bip(2-Me) Gly 349 H A D G Nle (D,L)-α-Me—Phe T S DBip(2-Et,4-OMe) Bip(2-Me) (penta- Fluoro) 350 H ala D G Nle(D,L)-α-Me—Phe T S D Bip(2-Et,4-OMe) Bip(2-Me) (penta- Fluoro) 351 H AibD G Nle (D,L)-α-Me—Phe T S D Bip(2-Et,4-OMe) Bip(2-Me) (penta- Fluoro)352 H ala E G T D—Phe(2,6-di- T S D Bip(2-Et) Bip(2-Me) Fluoro) 353 HAib D G T D—Phe(2,6-di- T S D Bip(2-Et) Bip(2-Me) Fluoro) 354 H A E G T(D,L)-α-Me—Phe T S D Bip(2-Et,4-OMe) Bip(2-Me) (penta- Fluoro) 355 H A DG T (D,L)-α-Me—Phe T S D Bip(2-Et,4-OMe) Bip(2-Me) (penta- Fluoro) 356 Hala E G T (D,L)-α-Me—Phe T S D Bip(2-Et,4-OMe) Bip(2-Me) (penta- Fluoro)357 H A D G T L-α-Me—Phe T S D Bip(2-Et) bip(2-Et) 358 H Aib D G TL-α-Me—Phe T S D Bip(2-Et) bip(2-Me) 359 H A E G T L-α-Me—Phe T S DBip(3-OH) Bip(2-Me) 360 H A E G T L-α-Me—Phe T S D Bip(4-OH) Bip(2-Me)361 H A E G T L-α-Me—Phe T S D Bip(2-OEt) Bip(2-Me) 362 H A E G TL-α-Me—Phe T S D Bip(3-OEt) Bip(2-Me) 363 H A E G T L-α-Me—Phe T S DBip(3-OCF3) Bip(2-Me) 364 H A E G T L-α-Me—Phe T S D Bip(3-NO2)Bip(2-Me) 365 H A E G T L-α-Me—Phe T S D Bip(3-CF3) Bip(2-Me) 366 H A EG T L-α-Me—Phe T S D Bip(3-F) Bip(2-Me) 367 H A E G T L-α-Me—Phe T S DBip(3-Cl) Bip(2-Me) 368 H A E G T L-α-Me—Phe T S D Bip(3-Ph) Bip(2-Me)369 H A E G T L-α-Me—Phe T S D Bip(3-Et) Bip(2-Me) 370 H A E G TL-α-Me—Phe T S D Bip(3-i—Pr) Bip(2-Me) 371 H A E G T L-α-Me—Phe T S DBip(4-i—Pr) Bip(2-Me) 372 H A E G T L-α-Me—Phe T S D Bip(4-Pr) Bip(2-Me)373 H A E G T L-α-Me—Phe T S D Bip(3-Pr) Bip(2-Me) 374 H A E G TL-α-Me—Phe T S D Bip(2,5-di—Cl) Bip(2-Me) 375 H A E G T L-α-Me—Phe T S DBip(2,5-di—F) Bip(2-Me) 376 H A E G T L-α-Me—Phe T S D Bip(3,4-di—F)Bip(2-Me) 377 H A E G T L-α-Me—Phe T S D Bip(3,4-di—Cl) Bip(2-Me) 378 HA E G T L-α-Me—Phe T S D Bip(2,3-di—Cl) Bip(2-Me) 379 H A E G TL-α-Me—Phe T S D Bip(3-NHAc) Bip(2-Me) 380 H A E G T L-α-Me—Phe T S DBip(4-NHAc) Bip(2-Me) 381 H A E G Aoc L-α-Me—Phe T S D Bip(2-Et)Bip(2-Me) 382 H A D G Nle F T S D Bip(2-Et) Bip(2-Me) 383 H ala E G TL—Phe(2-Fluoro) T S D Bip(2-Et) Bip(2-Me) 384 H Aib D G Nle(D,L)-α-Et—Phe T S D Bip(2-Et) Bip(2-Me) 385 H Aib D G T L-α-Me—Phe T(D, D Bip(2-Et) Bip(2-Me) L)- α- Me— Ser 386 H A D G T (L)-α-Me—Phe T SD Bip(2-Et,4-OMe) Bip(2-Me) 2,6-di- Fluoro) 387 H A E G T L-α-Me—Phe T SD Bip(4-t—Bu) Bip(2-Me) 388 H ala E G Nle (L)-α-Me—Phe T S DBip(2-Et,4-OMe) Bip(2-Me) (2,6-di- Fluoro) 389 H ala D G Nle(L)-α-Me—Phe T S D Bip(2-Et,4-OMe) Bip(2-Me) (2,6-di- Fluoro) 390 H AibE G Nle (L)-α-Me—Phe T S D Bip(2-Et,4-OMe) Bip(2-Me) (2,6-di- Fluoro)391 H Aib D G Nle (L)-α-Me—Phe T S D Bip(2-Et,4-OMe) Bip(2-Me) (2,6-di-Fluoro) 392 H A D G Nle (L)-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) (2,6-di-Fluoro) 393 H A D G T F T S D Bip(2-Et) Bip(2-Me)

[0181]

TABLE II [The peptides listed below are carboxamide at the C- terminus]Compou-nd # A Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 Xaa7 Xaa8 Xaa9 Y Z 1 AcetylH A E G T F T S D Bip Bip 2 β-Ala H A E G T F T S D Bip Bip 3 Ahx H A EG T F T S D Bip Bip 4 D H A E G T F T S D Bip Bip 5 E H A E G T F T S DBip Bip 6 F H A E G T F T S D Bip Bip 7 G H A E G T F T S D Bip Bip 8 KH A E G T F T S D Bip Bip 9 Nva H A E G T F T S D Bip Bip 10 N H A E G TF T S D Bip Bip 11 R H A E G T F T S D Bip Bip 12 S H A E G T F T S DBip Bip 13 T H A E G T F T S D Bip Bip 14 V H A E G T F T S D Bip Bip 15W H A E G T F T S D Bip Bip 16 Y H A E G T F T S D Bip Bip 17Caprolactam H A E G T F T S D Bip Bip 18 Bip H A E G T F T S D Bip Bip19 Ser(Bzl) H A E G T F T S D Bip Bip 20 3-PyridylAla H A E G T F T S DBip Bip 21 Phe(4-Me) H A E G T F T S D Bip Bip 22 Phe(pentafluoro) H A EG T F T S D Bip Bip

[0182] TABLE III

Compound # R-CH₂- Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 Xaa7 Xaa8 Xaa9 Y Z 14-Methylbenzyl H A E G T F T S D Bip(2-Me) Bip(2-Me) 2 4-Fluorobenzyl HA E G T F T S D Bip(2-Me) Bip(2-Me) 3 Propyl H A E G T F T S D Bip(2-Me)Bip(2-Me) 4 Hexyl H A E G T F T S D Bip(2-Me) Bip(2-Me) 5Cyclohexylmethyl H A E G T F T S D Bip(2-Me) Bip(2-Me) 6 6-HydroxypentylH A E G T F T S D Bip(2-Me) Bip(2-Me) 7 2-Thienylmethyl H A E G T F T SD Bip(2-Me) Bip(2-Me) 8 3-Thienylmethyl H A E G T F T S D Bip(2-Me)Bip(2-Me) 9 Pentafluorobenzyl H A E G T F T S D Bip(2-Me) Bip(2-Me) 102-Naphthylmethyl H A E G T F T S D Bip(2-Me) Bip(2-Me) 114-Biphenylmethyl H A E G T F T S D Bip(2-Me) Bip(2-Me) 129-Anthracenylmethyl H A E G T F T S D Bip(2-Me) Bip(2-Me) 13 Benzyl H AE G T F T S D Bip(2-Me) Bip(2-Me) 14 (S)-(2-Amino-3- H A E G T F T S DBip(2-Me) Bip(2-Me) phenyl)propyl 15 Methyl H A E G T F T S D Bip Bip 16Benzyl- H A E G T F T S D Bip Bip 17 2-aminoethyl H A E G T F T S DBip(2-Me) Bip(2-Me) 18 (S)-2-Aminopropyl H A E G T F T S D Bip(2-Me)Bip(2-Me) *All of the compounds in the Table were prepared as C-terminalcarboxamides.

[0183] TABLE IV Compound # Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 Xaa7 Xaa8 Xaa9Y Z B 1 H A E G T F T S D Bip 2-Nal W 2 H A E G T F T S D Bip Phe(penta-2-Nal Fluoro) 3 H A E G T F T S D Bip Phe(penta- Phe(penta- Fluoro)Fluoro) 4 H A E G T F T S D Bip Phe(penta- Ser(Bzl) Fluoro) 5 H A E G TF T S D Bip Phe(penta- Phe(4-NO₂) Fluoro) 6 H A E G T F T S D BipPhe(penta- 3-PyridylAla Fluoro) 7 H A E G T F T S D Bip Phe(penta- NvaFluoro) 8 H A E G T F T S D Bip Phe(penta- K Fluoro) 9 H A E G T F T S DBip Phe(penta- D Fluoro) 10 H A E G T F T S D Bip Phe(penta- S Fluoro)11 H A E G T F T S D Bip Phe(penta- H Fluoro) 12 H A E G T F T S D BipPhe(penta- Y Fluoro) 13 H A E G T F T S D Bip Phe(penta- W Fluoro) 14 HA E G T F T S D Bip Phe(penta- F Fluoro) 15 H A E G T F T S D 2-NalPhe(penta- W Fluoro) 16 H A E G T F T S D Bip Bip Bip 17 H A E G T F T SD Bip Bip Nva 18 H A E G T F T S D Bip(2- Bip(2-Me) ser Me) 19 H A E G TF T S D Bip(2- Bip(2-Me) Gly-OH Me) 20 H A E G T F T S D Bip(2-Bip(2-Me) β-Ala-OH Me) 21 H A E G T F T S D Bip(2- Bip(2-Me) GABA-OH Me)22 H A E G T F T S D Bip(2- Bip(2-Me) APA-OH Me) *All of the compoundsin the Table were prepared as C-terminal carboxamides, except forcompounds 19-22, which are carboxylic acids.

[0184] Additional compounds according to the present invention are shownhere in Table V. TABLE V Compound # A Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 Xaa7Xaa8 Xaa9 Y Z—NH2 1 Y H Aib E G T (L)-α- T S D Bip(2- Bip(2- Me—PheEt,4- Me)- (2- OMe) NH2 Fluoro) 2 Bip H Aib E G T (L)-α- T S D Bip(2-Bip(2- Me—Phe Et,4- Me)- (2- OMe) NH2 Fluoro) 3 CH₃CO H Aib E G T (L)-α-T S D Bip(2- Bip(2- Me—Phe Et,4- Me)- (2- OMe) NH2 Fluoro) 4 CH₃CH₂CO HAib E G T (L)-α- T S D Bip(2- Bip(2- Me—Phe Et,4- Me)- (2- OMe) NH2Fluoro) 5 Des—NH₂—Tyr H Aib E G T (L)-α- T S D Bip(2- Bip(2- Me—PheEt,4- Me)- (2- OMe) NH2 Fluoro) 6 CH₃OCO H Aib E G T (L)-α- T S D Bip(2-Bip(2- Me—Phe Et,4- Me)- (2- OMe) NH2 Fluoro) 7 CH₃NHCO H Aib E G T(L)-α- T S D Bip(2- Bip(2- Me—Phe Et,4- Me)- (2- OMe) NH2 Fluoro) 8CH₃SO₂ H Aib E G T (L)-α- T S D Bip(2- Bip(2- Me—Phe Et,4- Me)- (2- OMe)NH2 Fluoro) 9 (L)-OH—CH H Aib E G T (L)-α- T S D Bip(2- Bip(2- (CH₃)COMe—Phe Et,4- Me)- (2- OMe) NH2 Fluoro) 10 HO—CH₂—CO— H Aib E G T (L)-α-T S D Bip(2- Bip(2- Me—Phe Et,4- Me)- (2- OMe) NH2 Fluoro)

[0185] Additional compounds according to the present invention are shownhere in Table VI. TABLE VI Compound # Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 Xaa7Xaa8 Xaa9 Y Z B 1 H Aib E G T (L)-α- T S D Bip(2-Et,4- Bip(2-Me) Gly—OHMe—Phe OMe) (2- Fluoro) 2 H Aib E G T (L)-α- T S D Bip(2-Et,4- Bip(2-Me)β-Ala—OH Me—Phe OMe) (2- Fluoro) 3 H Aib E G T (L)-α- T S D Bip(2-Et,4-Bip(2-Me) GABA—OH Me—Phe OMe) (2- Fluoro)

EXAMPLE 12 Synthesis and Testing of a Peptide Corresponding to the“message” Sequence of GLP-1 and of the Same Peptide to Which an“address” Biphenylalanine Dipeptide Unit is Attached at the C-terminus

[0186] The peptide corresponding to the N-terminal 1-9 sequence ofGLP-1, His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-NH2, which in this inventionis referred to as the “message” sequence of GLP-1, and the GLP-1 11-merpeptide analog His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Bip-Bip-NH2, which iscomprised of the message sequence of GLP-1 and of a C-terminalbiphenylalanine dipeptide unit, were prepared using the methodsdescribed herein and tested in the cAMP cell-based assay describe inExample 13. The GLP-1 11-mer peptide analog stimulated cAMP productionin a dose-response manner corresponding to an EC₅₀ value of 1.1micromolar, determined as in Example 13. In the same assay, the EC₅₀value determined for the peptide corresponding to the “message” sequenceof GLP-1 was greater than 1 millimolar. The EC₅₀ value for GLP-1, usedin the assay as a positive control, was less than 0.100 nanomolar.

EXAMPLE 13 Cyclic AMP Determination

[0187] The GLP-1 receptor is a G-protein coupled receptor. GLP-1(7-36)-amide, the biologically active form, binds to the GLP-1 receptorand through signal transduction causes activation of adenylate cyclaseand raises intracellular cAMP levels. To monitor agonism of peptidecompounds in stimulating the GLP-1 receptor, adenyl cyclase activity wasmonitored by assaying for cellular cAMP levels. Full-length humanglucagon-like peptide 1 receptor was stably expressed in CHO-K1 cells.The clones were screened for best expression of GLP-1R and CHO-GLP1R-19was selected. Cells were cultured in Ham's F12 nutritional media (Gibco#11765-054), 10% FBS, 1× L-Glutamine, 1× Pen/Strep, and 0.4 mg/ml G418.CHO-GLP-1R-19 cells (2,500 in 100 μl of media) were plated into eachwell of a 96-well tissue culture microtiter plate and incubated in 5%CO₂ atmosphere at 37° C., for 72 h. On the day of the assay, cells werewashed once with 100 μl of PBS. To cells in each well, 10 μl of compoundand 90 μl of reaction media (Phenol red free DMEM media with low glucose(Gibco#11054-020), 0.1% BSA (Sigma #A7284), 0.3 mM IBMX (3-isobutyl-1methylxanthine, Sigma #I5879) were added and incubated at 37° C. for 1h. The compounds were initially screened at 1 μM and 10 μM forstimulation of cAMP. Dose dependence for compounds showing 50% ofmaximal GLP-1 (at 100 nM) activity was determined at half-logconcentrations in duplicate. After incubation, medium was removed andcells were washed once with 100 μl of PBS. Fifty μl of lysis reagent-1from the cyclic AMP SPA kit (Amersham Pharmacia Biotech, RPA 559;reagents were reconstituted according to the kit instructions) was addedinto each well. The plate was shaken at room temperature for 15 min.Twenty μl of lysate was transferred into each well of a 96-wellOptiPlate (Packard #6005190) and 60 μl of SPA immunoreagent from the kitwas added. After incubation at room temperature for 15-18 h, plates werecounted 2 min each/well in a TopCount NXT(Packard).

[0188] In each 96-well plate, GLP-1 (control), and five compounds (induplicate) were run at seven half-log doses. Ten nM GLP-1 was platedinto ten additional wells to serve as a reference standard fordetermination of maximal activity. The data obtained was processed inExcel-fit database. From a cyclic AMP standard curve, the amounts ofreleased cAMP were determined and the % maximal activity was calculatedand plotted against log compound concentration. The data was analyzed bynonlinear regression curve fit (sigmoidal dose) to determine the EC₅₀ofthe compounds.

EXAMPLE 14 In-Vivo Studies

[0189] The in-vivo glucose lowering properties for four representative11-mer peptides, compound A, compound B, compound C and compound D in arat model is described below. Continuous intravenous infusion ofcompound A and compound B significantly attenuated the postprandialglucose excursion curve in subcutaneous glucose tolerance test (scGTT)(see FIG. 1 and FIG. 2). In addition, these two 11-mer peptidesadministered by subcutaneous injection also produced a significantglucose lowering effect in this model (see FIG. 3 and FIG. 4). A cleardose-response relationship was observed following both continuousintravenous infusion and subcutaneous bolus injection of the analogs fortheir glucose lowering effects. The significant glucose lowering effectfor compound A and compound B was observed at 12 and 120 pmol/kg/min,respectively, when the compound was administered by continuous infusion.For the subcutaneous administration, the maximum effective doses forCompound A and Compound B were about 2 and 20 nmol/kg, respectively.

[0190] For compounds C and D, studies using subcutaneous injection in arat intraperitoneal glucose tolerance test (ipGTT) model showed thatsignificant glucose excursion attenuation could be achieved for bothcompounds in a dose-related fashion (see FIGS. 5 and 6). FIG. 7 showsthe effects of native GLP-1 in this model.

UTILITY & COMBINATIONS

[0191] A. Utilities

[0192] The present invention provides novel GLP peptide mimics, with apreference for mimicking GLP-1, such that the compounds of the presentinvention have agonist activity for the GLP-1 receptor. Further, the GLPpeptide mimics of the present invention exhibit incresased stability toproteolytic cleavage as compared to GLP-1 native sequences.

[0193] Accordingly, the compounds of the present invention can beadministered to mammals, preferably humans, for the treatment of avariety of conditions and disorders, including, but not limited to,treating or delaying the progression or onset of diabetes (preferablyType II, impaired glucose tolerance, insulin resistance, and diabeticcomplications, such as nephropathy, retinopathy, neuropathy andcataracts), hyperglycemia, hyperinsulinemia, hypercholesterolemia,elevated blood levels of free fatty acids or glycerol, hyperlipidemia,hypertriglyceridemia, obesity, wound healing, tissue ischemia,atherosclerosis, hypertension, AIDS, intestinal diseases (such asnecrotizing enteritis, microvillus inclusion disease or celiac disease),inflammatory bowel syndrome, chemotherapy-induced intestinal mucosalatrophy or injury, anorexia nervosa, osteoporosis, dysmetabolicsyndrome, as well as inflammatory bowel disease (such as Crohn's diseaseand ulcerative colitis). The compounds of the present invention may alsobe utilized to increase the blood levels of high density lipoprotein(HDL).

[0194] In addition, the conditions, diseases, and maladies collectivelyreferenced to as “Syndrome X” or Metabolic Syndrome as detailed inJohannsson J. Clin. Endocrinol. Metab., 82, 727-34 (1997), may betreated employing the compounds of the invention.

[0195] B. Combinations

[0196] The present invention includes within its scope pharmaceuticalcompositions comprising, as an active ingredient, a therapeuticallyeffective amount of at least one of the compounds of formula I, alone orin combination with a pharmaceutical carrier or diluent. Optionally,compounds of the present invention can be used alone, in combinationwith other compounds of the invention, or in combination with one ormore other therapeutic agent(s), e.g., an antidiabetic agent or otherpharmaceutically active material.

[0197] The compounds of the present invention may be employed incombination with other GLP-1 peptide mimics or other suitabletherapeutic agents useful in the treatment of the aforementioneddisorders including: anti-diabetic agents; anti-hyperglycemic agents;hypolipidemic/lipid lowering agents; anti-obesity agents (includingappetite supressants/modulators) and anti-hypertensive agents. Inaddition, the compounds of the present invention may be combined withone or more of the following therapeutic agents; infertility agents,agents for treating polycystic ovary syndrome, agents for treatinggrowth disorders, agents for treating frailty, agents for treatingarthritis, agents for preventing allograft rejection in transplantation,agents for treating autoimmune diseases, anti-AIDS agents,anti-osteoporosis agents, agents for treating immunomodulatory diseases,antithrombotic agents, agents for the treatment of cardiovasculardisease, antibiotic agents, anti-psychotic agents, agents for treatingchronic inflammatory bowel disease or syndrome and/or agents fortreating anorexia nervosa.

[0198] Examples of suitable anti-diabetic agents for use in combinationwith the compounds of the present invention include biguanides (e.g.,metformin or phenformin), glucosidase inhibitors (e.g, acarbose ormiglitol), insulins (including insulin secretagogues or insulinsensitizers), meglitinides (e.g., repaglinide), sulfonylureas (e.g.,glimepiride, glyburide, gliclazide, chlorpropamide and glipizide),biguanide/glyburide combinations (e.g., Glucovance®), thiazolidinediones(e.g., troglitazone, rosiglitazone and pioglitazone), PPAR-alphaagonists, PPAR-gamma agonists, PPAR alpha/gamma dual agonists, glycogenphosphorylase inhibitors, inhibitors of fatty acid binding protein(aP2), DPP-IV inhibitors, and SGLT2 inhibitors.

[0199] Other suitable thiazolidinediones include Mitsubishi's MCC-555(disclosed in U.S. Pat. No. 5,594,016), Glaxo-Welcome's GL-262570,englitazone (CP-68722, Pfizer) or darglitazone (CP-86325, Pfizer,isaglitazone (MIT/J&J), JTT-501 (JPNT/P&U), L-895645 (Merck), R-119702(Sankyo/WL), NN-2344 (Dr. Reddy/NN), or YM-440 (Yamanouchi).

[0200] Suitable PPAR alpha/gamma dual agonists include AR-HO39242(Astra/Zeneca), GW-409544 (Glaxo-Wellcome), KRP297 (Kyorin Merck) aswell as those disclosed by Murakami et al, “A Novel Insulin SensitizerActs As a Coligand for Peroxisome Proliferation—Activated Receptor Alpha(PPAR alpha) and PPAR gamma. Effect on PPAR alpha Activation on AbnormalLipid Metabolism in Liver of Zucker Fatty Rats”, Diabetes 47, 1841-1847(1998), and in U.S. application Ser. No. 09/644,598, filed Sep. 18,2000, the disclosure of which is incorporated herein by reference,employing dosages as set out therein, which compounds designated aspreferred are preferred for use herein.

[0201] Suitable aP2 inhibitors include those disclosed in U.S.application Ser. No. 09/391,053, filed Sep. 7, 1999, and in U.S.application Ser. No. 09/519,079, filed Mar. 6, 2000, employing dosagesas set out herein.

[0202] Suitable DPP4 inhibitors that may be used in combination with thecompounds of the invention include those disclosed in WO99/38501,WO99/46272, WO99/67279 (PROBIODRUG), WO99/67278 (PROBIODRUG), WO99/61431(PROBIODRUG), NVP-DPP728A(1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine)(Novartis) as disclosed by Hughes et al, Biochemistry, 38(36),11597-11603, 1999, TSL-225(tryptophyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (disclosedby Yamada et al, Bioorg. & Med. Chem. Lett. 8 (1998) 1537-1540,2-cyanopyrrolidides and 4-cyanopyrrolidides, as disclosed by Ashworth etal, Bioorg. & Med. Chem. Lett., Vol. 6, No. 22, pp 1163-1166 and2745-2748 (1996) employing dosages as set out in the above references.

[0203] Suitable meglitinides include nateglinide (Novartis) or KAD1229(PF/Kissei).

[0204] Examples of other suitable glucagon-like peptide-1 (GLP-1, )compounds that may be used in combination with the GLP-1 mimics of thepresent invention include GLP-1(1-36) amide, GLP-1(7-36) amide,GLP-1(7-37) (as disclosed in U.S. Pat. No. 5,614,492 to Habener), aswell as AC2993 (Amylin), LY-315902 (Lilly) and NN-2211 (NovoNordisk).

[0205] Examples of suitable hypolipidemic/lipid lowering agents for usein combination with the compounds of the present invention include oneor more MTP inhibitors, HMG CoA reductase inhibitors, squalenesynthetase inhibitors, fibric acid derivatives, ACAT inhibitors,lipoxygenase inhibitors, cholesterol absorption inhibitors, ilealNa⁺/bile acid cotransporter inhibitors, upregulators of LDL receptoractivity, bile acid sequestrants, cholesterol ester transfer proteininhibitors (e.g., CP-529414 (Pfizer)) and/or nicotinic acid andderivatives thereof.

[0206] MTP inhibitors which may be employed as described above includethose disclosed in U.S. Pat. No. 5,595,872, U.S. Pat. No. 5,739,135,U.S. Pat. No. 5,712,279, U.S. Pat. No. 5,760,246, U.S. Pat. No.5,827,875, U.S. Pat. No. 5,885,983 and U.S. Pat. No. 5,962,440.

[0207] The HMG CoA reductase inhibitors which may be employed incombination with one or more compounds of formula I include mevastatinand related compounds, as disclosed in U.S. Pat. No. 3,983,140,lovastatin (mevinolin) and related compounds, as disclosed in U.S. Pat.No. 4,231,938, pravastatin and related compounds, such as disclosed inU.S. Pat. No. 4,346,227, simvastatin and related compounds, as disclosedin U.S. Pat. Nos. 4,448,784 and 4,450,171. Other HMG CoA reductaseinhibitors which may be employed herein include, but are not limited to,fluvastatin, disclosed in U.S. Pat. No. 5,354,772, cerivastatin, asdisclosed in U.S. Pat. Nos. 5,006,530 and 5,177,080, atorvastatin, asdisclosed in U.S. Pat. Nos. 4,681,893, 5,273,995, 5,385,929 and5,686,104, atavastatin (Nissan/Sankyo's nisvastatin (NK-104)), asdisclosed in U.S. Pat. No. 5,011,930, visastatin (Shionogi-Astra/Zeneca(ZD-4522)), as disclosed in U.S. Pat. No. 5,260,440, and related statincompounds disclosed in U.S. Pat. No. 5,753,675, pyrazole analogs ofmevalonolactone derivatives, as disclosed in U.S. Pat. No. 4,613,610,indene analogs of mevalonolactone derivatives, as disclosed in PCTapplication WO 86/03488,6-[2-(substituted-pyrrol-1-yl)-alkyl)pyran-2-ones and derivativesthereof, as disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355 (a3-substituted pentanedioic acid derivative) dichloroacetate, imidazoleanalogs of mevalonolactone, as disclosed in PCT application WO 86/07054,3-carboxy-2-hydroxy-propane-phosphonic acid derivatives, as disclosed inFrench Patent No. 2,596,393, 2,3-disubstituted pyrrole, furan andthiophene derivatives, as disclosed in European Patent Application No.0221025, naphthyl analogs of mevalonolactone, as disclosed in U.S. Pat.No. 4,686,237, octahydronaphthalenes, such as disclosed in U.S. Pat. No.4,499,289, keto analogs of mevinolin (lovastatin), as disclosed inEuropean Patent Application No. 0142146 A2, and quinoline and pyridinederivatives, as disclosed in U.S. Pat. Nos. 5,506,219 and 5,691,322.

[0208] Preferred hypolipidemic agents are pravastatin, lovastatin,simvastatin, atorvastatin, fluvastatin, cerivastatin, atavastatin andZD-4522.

[0209] In addition, phosphinic acid compounds useful in inhibiting HMGCoA reductase, such as those disclosed in GB 2205837, are suitable foruse in combination with the compounds of the present invention.

[0210] The squalene synthetase inhibitors suitable for use hereininclude, but are not limited to, α-phosphono-sulfonates disclosed inU.S. Pat. No. 5,712,396, those disclosed by Biller et al, J. Med. Chem.,1988, Vol. 31, No. 10, pp 1869-1871, including isoprenoid(phosphinyl-methyl)phosphonates, as well as other known squalenesynthetase inhibitors, for example, as disclosed in U.S. Pat. Nos.4,871,721 and 4,924,024 and in Biller, S. A., Neuenschwander, K.,Ponpipom, M. M., and Poulter, C. D., Current Pharmaceutical Design, 2,1-40 (1996).

[0211] In addition, other squalene synthetase inhibitors suitable foruse herein include the terpenoid pyrophosphates disclosed by P. Ortiz deMontellano et al, J. Med. Chem., 1977, 20, 243-249, the farnesyldiphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs asdisclosed by Corey and Volante, J. Am. Chem. Soc., 1976, 98, 1291-1293,phosphinylphosphonates reported by McClard, R. W. et al, J.A.C.S., 1987,109, 5544 and cyclopropanes reported by Capson, T. L., PhD dissertation,June, 1987, Dept. Med. Chem. U of Utah, Abstract, Table of Contents, pp16, 17, 40-43, 48-51, Summary.

[0212] The fibric acid derivatives which may be employed in combinationwith one or more compounds of formula I include fenofibrate,gemfibrozil, clofibrate, bezafibrate, ciprofibrate, clinofibrate and thelike, probucol, and related compounds, as disclosed in U.S. Pat. No.3,674,836, probucol and gemfibrozil being preferred, bile acidsequestrants, such as cholestyramine, colestipol and DEAE-Sephadex(Secholex®, Policexide®), as well as lipostabil (Rhone-Poulenc), EisaiE-5050 (an N-substituted ethanolamine derivative), imanixil (HOE-402),tetrahydrolipstatin (THL), istigmastanylphos-phorylcholine (SPC, Roche),aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulenederivative), melinamide (Sumitomo), Sandoz 58-035, American CyanamidCL-277,082 and CL-283,546 (disubstituted urea derivatives), nicotinicacid, acipimox, acifran, neomycin, p-aminosalicylic acid, aspirin,poly(diallylmethylamine) derivatives, such as disclosed in U.S. Pat. No.4,759,923, quaternary amine poly(diallyldimethylammonium chloride) andionenes, such as disclosed in U.S. Pat. No. 4,027,009, and other knownserum cholesterol lowering agents.

[0213] The ACAT inhibitor which may be employed in combination with oneor more compounds of formula I include those disclosed in Drugs of theFuture 24, 9-15 (1999), (Avasimibe); “The ACAT inhibitor, Cl-1011 iseffective in the prevention and regression of aortic fatty streak areain hamsters”, Nicolosi et al, Atherosclerosis (Shannon, Irel). (1998),137(1), 77-85; “The pharmacological profile of FCE 27677: a novel ACATinhibitor with potent hypolipidemic activity mediated by selectivesuppression of the hepatic secretion of ApoB100-containing lipoprotein”,Ghiselli, Giancarlo, Cardiovasc. Drug Rev. (1998), 16(1), 16-30; “RP73163: a bioavailable alkylsulfinyl-diphenylimidazole ACAT inhibitor”,Smith, C., et al, Bioorg. Med. Chem. Lett. (1996), 6(1), 47-50; “ACATinhibitors: physiologic mechanisms for hypolipidemic andanti-atherosclerotic activities in experimental animals”, Krause et al,Editor(s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A.,Inflammation: Mediators Pathways (1995), 173-98, Publisher: CRC, BocaRaton, Fla.; “ACAT inhibitors: potential anti-atherosclerotic agents”,Sliskovic et al, Curr. Med. Chem. (1994), 1(3), 204-25; “Inhibitors ofacyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemicagents. 6. The first water-soluble ACAT inhibitor with lipid-regulatingactivity. Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). 7.Development of a series of substitutedN-phenyl-N′-[(1-phenylcyclopentyl)methyl]ureas with enhancedhypocholesterolemic activity”, Stout et al, Chemtracts: Org. Chem.(1995), 8(6), 359-62, or TS-962 (Taisho Pharmaceutical Co. Ltd).

[0214] The hypolipidemic agent may be an upregulator of LD2 receptoractivity, such as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427(Eli Lilly).

[0215] Examples of suitable cholesterol absorption inhibitor for use incombination with the compounds of the invention include SCH48461(Schering-Plough), as well as those disclosed in Atherosclerosis 115,45-63 (1995) and J. Med. Chem. 41, 973 (1998).

[0216] Examples of suitable ileal Na⁺/bile acid cotransporter inhibitorsfor use in combination with the compounds of the invention includecompounds as disclosed in Drugs of the Future, 24, 425-430 (1999).

[0217] The lipoxygenase inhibitors which may be employed in combinationwith one or more compounds of formula I include 15-lipoxygenase (15-LO)inhibitors, such as benzimidazole derivatives, as disclosed in WO97/12615, 15-LO inhibitors, as disclosed in WO 97/12613, isothiazolones,as disclosed in WO 96/38144, and 15-LO inhibitors, as disclosed bySendobry et al “Attenuation of diet-induced atherosclerosis in rabbitswith a highly selective 15-lipoxygenase inhibitor lacking significantantioxidant properties”, Brit. J. Pharmacology (1997) 120, 1199-1206,and Cornicelli et al, “15-Lipoxygenase and its Inhibition: A NovelTherapeutic Target for Vascular Disease”, Current Pharmaceutical Design,1999, 5, 11-20.

[0218] Examples of suitable anti-hypertensive agents for use incombination with the compounds of the present invention include betaadrenergic blockers, calcium channel blockers (L-type and T-type; e.g.diltiazem, verapamil, nifedipine, amlodipine and mybefradil), diuretics(e.g., chlorothiazide, hydrochlorothiazide, flumethiazide,hydroflumethiazide, bendroflumethiazide, methylchlorothiazide,trichloromethiazide, polythiazide, benzthiazide, ethacrynic acidtricrynafen, chlorthalidone, furosemide, musolimine, bumetanide,triamtrenene, amiloride, spironolactone), renin inhibitors, ACEinhibitors (e.g., captopril, zofenopril, fosinopril, enalapril,ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril,lisinopril), AT-1 receptor antagonists (e.g., losartan, irbesartan,valsartan), ET receptor antagonists (e.g., sitaxsentan, atrsentan andcompounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265), DualET/AII antagonist (e.g., compounds disclosed in WO 00/01389), neutralendopeptidase (NEP) inhibitors, vasopepsidase inhibitors (dual NEP-ACEinhibitors) (e.g., omapatrilat and gemopatrilat), and nitrates.

[0219] Examples of suitable anti-obesity agents for use in combinationwith the compounds of the present invention include a NPY receptorantagonist, a MCH antagonist, a GHSR antagonist, a CRH antagonist, abeta 3 adrenergic agonist, a lipase inhibitor, a serotonin (anddopamine) reuptake inhibitor, a thyroid receptor beta drug and/or ananorectic agent.

[0220] The beta 3 adrenergic agonists which may be optionally employedin combination with compounds of the present invention include AJ9677(Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer,) or otherknown beta 3 agonists, as disclosed in U.S. Pat. Nos. 5,541,204,5,770,615, 5,491,134, 5,776,983 and 5,488,064, with AJ9677, L750,355 andCP331648 being preferred.

[0221] Examples of lipase inhibitors which may be optionally employed incombination with compounds of the present invention include orlistat orATL-962 (Alizyme), with orlistat being preferred.

[0222] The serotonin (and dopoamine) reuptake inhibitor which may beoptionally employed in combination with a compound of formula I may besibutramine, topiramate (Johnson & Johnson) or axokine (Regeneron), withsibutramine and topiramate being preferred.

[0223] Examples of thyroid receptor beta compounds which may beoptionally employed in combination with compounds of the presentinvention include thyroid receptor ligands, such as those disclosed inWO97/21993 (U. Cal SF), WO99/00353 (KaroBio) and GB98/284425 (KaroBio),with compounds of the KaroBio applications being preferred.

[0224] The anorectic agent which may be optionally employed incombination with compounds of the present invention includedexamphetamine, phentermine, phenylpropanolamine or mazindol, withdexamphetamine being preferred.

[0225] Examples of suitable anti-psychotic agents include clozapine,haloperidol, olanzapine (Zyprexa®) , Prozaco® and aripiprazole(Abilify®).

[0226] The aforementioned patents and patent applications areincorporated herein by reference.

[0227] The above other therapeutic agents, when employed in combinationwith the compounds of the present invention may be used, for example, inthose amounts indicated in the Physician's Desk Reference, as in thepatents set out above or as otherwise determined by one of ordinaryskill in the art.

Dosage And Formulation

[0228] A suitable GLP-1 peptide mimic can be administered to patients totreat diabetes and other related diseases as the compound alone and ormixed with an acceptable carrier in the form of pharmaceuticalformulations. Those skilled in the art of treating diabetes can easilydetermine the dosage and route of administration of the compound tomammals, including humans, in need of such treatment. The route ofadministration may include but is not limited to oral, intraoral,rectal, transdermal, buccal, intranasal, pulmonary, subcutaneous,intramuscular, intradermal, sublingual, intracolonic, intraoccular,intravenous, or intestinal administration. The compound is formulatedaccording to the route of administration based on acceptable pharmacypractice (Fingl et al., in The Pharmacological Basis of Therapeutics,Ch. 1, p.1, 1975; Remington's Pharmaceutical Sciences, 18^(th) ed., MackPublishing Co, Easton, Pa., 1990).

[0229] The pharmaceutically acceptable GLP-1 peptide mimic compositionof the present invention can be administered in multiple dosage formssuch as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs, in situgels, microspheres, crystalline compleses, liposomes, micro-emulsions,tinctures, suspensions, syrups, aerosol sprays and emulsions. Thecomposition of the present invention can also be administered in oral,intravenous (bolus or infusion), intraperitoneal, subcutaneous,transdermally or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. The compositionmay be administered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

[0230] The dosage regimen for the composition of the present inventionwill, of course, vary depending upon known factors, such as thepharmacodynamic characteristics of the particular agent and its mode androute of administration; the species, age, sex, health, medicalcondition, and weight of the recipient; the nature and extent of thesymptoms; the kind of concurrent treatment; the frequency of treatment;the route of administration, the renal and hepatic function of thepatient, and the effect desired. A physician or veterinarian candetermine and prescribe the effective amount of the drug required toprevent, counter, or arrest the progress of the disease state.

[0231] By way of general guidance, the daily oral dosage of the activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, preferably between about 0.01to 100 mg/kg of body weight per day, and most preferably between about0.6 to 20 mg/kg/day. Intravenously, the daily dosage of the activeingredient when used for the indicated effects will range between 0.001ng to 100.0 ng per min/per Kg of body weight during a constant rateinfusion. Such constant intravenous infusion can be preferablyadministered at a rate of 0.01 ng to 50 ng per min per Kg body weightand most preferably at 0.1 ng to 10.0 mg per min per Kg body weight. Thecomposition of this invention may be administered in a single dailydose, or the total daily dosage may be administered in divided doses oftwo, three, or four times daily. The composition of this invention mayalso be administered by a depot formulation that will allow sustainedrelease of the drug over a period of days/weeks/months as desired.

[0232] The composition of this invention can be administered inintranasal form via topical use of suitable intranasal vehicles, or viatransdermal routes, using transdermal skin patches. When administered inthe form of a transdermal delivery system, the dosage administrationwill, of course, be continuous rather than intermittent throughout thedosage regimen.

[0233] The composition is typically administered in a mixture withsuitable pharmaceutical diluents, excipients, or carriers (collectivelyreferred to herein as pharmaceutical carriers) suitably selected withrespect to the intended form of administration, that is, oral tablets,capsules, elixirs, aerosol sprays generated with or without propallantand syrups, and consistent with conventional pharmaceutical practices.

[0234] For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as but notlimited to, lactose, starch, sucrose, glucose, methyl cellulose,magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, andsorbitol; for oral administration in liquid form, the oral drugcomponents can be combined with any oral, non-toxic, pharmaceuticallyacceptable inert carrier such as, but not limited to, ethanol, glycerol,and water. Moreover, when desired or necessary, suitable binders,lubricants, disintegrating agents, and coloring agents can also beincorporated into the mixture. Suitable binders include, but not limitedto, starch, gelatin, natural sugars such as, but not limited to, glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, and waxes. Lubricants used in these dosage formsinclude sodium oleate, sodium stearate, magnesium stearate, sodiumbenzoate, sodium acetate, and sodium chloride. Disintegrants include,but are not limited to, starch, methyl cellulose, agar, bentonite, andxanthan gum.

[0235] The composition of the present invention may also be administeredin the form of mixed micellar or liposome delivery systems, such assmall unilamellar vesicles, large unilamellar vesicles, andmultilamellar vesicles. Liposomes can be formed from a variety ofphospholipids, such as cholesterol, stearylamine, orphosphatidylcholines. Permeation enhancers may be added to enhance drugabsorption.

[0236] Since prodrugs are known to enhance numerous desirable qualitiesof pharmaceuticals (i.e., solubility, bioavailability, manufacturing,etc.) the compounds of the present invention may be delivered in prodrugform. Thus, the present invention is intended to cover prodrugs of thepresently claimed compounds, methods of delivering the same andcompositions containing the same.

[0237] The compositions of the present invention may also be coupledwith soluble polymers as targetable drug carriers. Such polymers caninclude polyvinyl-pyrrolidone, pyran copolymer,polyhydroxypropyl-methacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the composition of thepresent invention may be combined with a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

[0238] Dosage forms (pharmaceutical compositions) suitable foradministration may contain from about 0.1 milligram to about 500milligrams of active ingredient per dosage unit. In these pharmaceuticalcompositions the active ingredient will ordinarily be present in anamount of about 0.5-95% by weight based on the total weight of thecomposition.

[0239] Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivative, magnesiumstearate, and stearic acid. Similar diluents can be used to makecompressed tablets. Both tablets and capsules can be manufactured assustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

[0240] Liquid dosage forms for oral administration can contain coloringand flavoring to increase patient acceptance.

[0241] In general, water, a suitable oil, saline, aqueous dextrose(glucose), and related sugar solutions and glycols such as propyleneglycol or polyethylene glycols are suitable carriers for parenteralsolutions. Solution for parenteral administration preferably contains awater-soluble salt of the active ingredient, suitable stabilizingagents, and if necessary, buffer substances. Antioxidizing agents suchas sodium bisulfite, sodium sulfite, or ascorbic acid, either alone orcombined, are suitable stabilizing agents. Also used are citric acid andits salts and sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

[0242] Suitable pharmaceutical carriers are described in Remington: TheScience and Practice of Pharmacy, Nineteenth Edition, Mack PublishingCompany, 1995, a standard reference text in this field

[0243] Representative useful pharmaceutical dosage forms foradministration of the compound of this invention can be illustrated asfollows:

Capsules

[0244] A large number of unit capsules can be prepared by fillingstandard two-piece hard gelatin capsules with 100 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

[0245] A mixture of active ingredient in a digestable oil such assoybean oil, cottonseed oil or olive oil may be prepared and injected bymeans of a positive displacement pump into gelatin to form soft gelatincapsules containing 100 milligrams of the active ingredient. Thecapsules should be washed and dried.

Tablets

[0246] Tablets may be prepared by conventional procedures so that thedosage unit, for example is 100 milligrams of active ingredient, 0.2milligrams of colloidal silicon dioxide, 5 milligrams of magnesiumstearate, 275 milligrams of microcrystalline cellulose, 11 milligrams ofstarch and 98.8 milligrams of lactose. Appropriate coatings may beapplied to increase palatability or delay absorption.

Injectable

[0247] A parenteral composition suitable for administration by injectionmay be prepared by stirring for example, 1.5% by weight of activeingredient in 10% by volume propylene glycol and water. The solutionshould be made isotonic with sodium chloride and sterilized.

Suspension

[0248] An aqueous suspension can be prepared for oral and/or parenteraladministration so that, for example, each 5 mL contains 100 mg of finelydivided active ingredient, 20 mg of sodium carboxymethyl cellulose, 5 mgof sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 mL ofvanillin or other palatable flavoring.

Biodegradable Microparticles

[0249] A sustained-release parenteral composition suitable foradministration by injection may be prepared, for example, by dissolvinga suitable biodegradable polymer in a solvent, adding to the polymersolution the active agent to be incorporated, and removing the solventfrom the matrix thereby forming the matrix of the polymer with theactive agent distributed throughout the matrix.

[0250] Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeunderstood that within the scope of the appended claims, the inventionmay be practiced otherwise than as specifically described herein.

[0251] The present invention is not to be limited in scope by thespecific embodiments described that are intended as single illustrationsof individual aspects of the invention. Functionally equivalent methodsand components in addition to those shown and described herein willbecome apparent to those skilled in the art from the foregoingdescription and accompanying drawings. Such modifications are intendedto fall within the scope of the appended claims.

1 6 1 9 PRT Artificial naturally or non-naturally occurring 1 Xaa XaaXaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 2 2 PRT Artificial naturally ornon-naturally occurring 2 Xaa Xaa 1 3 9 PRT Artificial naturally ornon-naturally occurring 3 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 4 8PRT Artificial naturally or non-naturally occurring 4 Xaa Xaa Xaa XaaXaa Xaa Xaa Xaa 1 5 5 8 PRT Artificial naturally or non-naturallyoccurring 5 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 6 8 PRT Artificialnaturally or non-naturally occurring 6 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 15

What is claimed is:
 1. An isolated polypeptide having a sequence ofFormula IA-X_(aa1)—X_(aa2)—X_(aa3)—X_(aa4)—X_(aa5)—X_(aa6)—X_(aa7)—X_(aa8)—X_(aa9)—Y-Z-B  I wherein, X_(aa1-9) is a naturally or nonnaturally occurring aminoacid residue; Y and Z are amino acid residues; wherein one of thesubstitutions at the alpha-carbon atoms of Y and Z may eachindependently be substituted with a primary substituent group selectedfrom the group consisting of hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl,heterocyclylalkyl said primary substituent optionally being substitutedwith a secondary substituent selected from a cycloalkyl, heterocyclyl,aryl or heteroaryl group; any of said primary or secondary substituentsmay further be substituted with one or more of, hydrogen, alkyl,cycloalkyl, arylalkyl, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl,halo, hydroxy, mercapto, nitro, cyano, amino, acylamino, azido,guanidino, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl,acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy,heterocycleoxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl,mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl,guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl orphosphonic group; wherein, the primary or secondary substitutents mayoptionally be bridged by covalent bonds to form one or more fused cyclicor heterocyclic systems with each other; wherein, the other substitutionat the alpha-carbon of Y may be substituted with hydrogen, alkyl,aminoalkyl, hydroxyalkyl or carboxyalkyl; wherein, the othersubstitution at the alpha-carbon of Z may be substituted with hydrogen,alkyl, aminoalkyl, hydroxyalkyl or carboxyalkyl; A and B are optionallypresent; wherein A is present and A is hydrogen, an amino acid orpeptide containing from about 1 to about 15 amino acid residues, an Rgroup, an R—C(O) (amide) group, a carbamate group RO—C (O), a ureaR₄R₅N—C(O), a sulfonamido R—SO₂, or a R₄R₅N—SO₂; wherein R is selectedfrom the group consisting of hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl,arylalkyl, aryloxyalkyl, heteroarylalkyl and heteroaryloxyalkyl; whereinR₄ and R₅ are each independently selected from the group consisting ofhydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl,heteroarylalkyl and heteroaryloxyalky; wherein the alpha-amino group ofX_(aa1) is substituted with a hydrogen or an alkyl group, said alkylgroup may optionally form a ring with A; wherein B is present and B isOR₁, NR₁R₂, or an amino acid or peptide containing from 1 to 15 aminoacid residues, terminating at the C-terminus as a carboxamide,substituted carboxamide, an ester, a free carboxylic acid or anamino-alcohol; wherein R₁ and R₂ are independently chosen from hydrogen,alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl,aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl orheteroaryloxyalkyl.
 2. The isolated polypeptide of claim 1 wherein thesubstitutions upon the alpha-carbon atoms of Y and Z are selected fromthe group consisting of heteroarylarylmethyl, arylheteroarylmethyl orbiphenylmethyl forming biphenylalanine residues, any of which is alsooptionally substituted with one or more, hydrogen, alkyl, cycloalkyl,arylalkyl, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl, halo,hydroxy, mercapto, nitro, cyano, amino, acylamino, azido, guanidino,amidino, carboxyl, carboxamido, carboxamido alkyl, formyl, acyl,carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy,heterocycleoxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl,mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl,guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl andphosphonic group.
 3. The isolated polypeptide of claim 1 wherein B is anamino acid or peptide containing 1 to about 10 amino acid residues. 4.The isolated polypeptide of claim 3 wherein B is an amino acid orpeptide containing 1 to about 5 amino acid residues.
 5. The isolatedpolypeptide of claim 1 wherein X_(aa1), X_(aa2) and X_(aa3) are N—H orN-alkylated amino acid residues.
 6. The isolated polypeptide of claim 5wherein X_(aa1), X_(aa2) and X_(aa3) are N—H or N-methylated amino acidresidues.
 7. The isolated polypeptide of claim 1 wherein the othersubstitution at the alpha-carbon of Y is substituted with hydrogen,methyl or ethyl; and wherein, the other substitution at the alpha-carbonof Z is substituted with hydrogen, methyl or ethyl.
 8. The isolatedpolypeptide of claim 1 wherein X_(aa1) is naturally or nonnaturallyoccurring amino acid residue in which one of the substitutions at thealpha-carbon is a primary substituent selected from the group consistingof heterocyclylalkyl, heteroaryl, heteroarylkalkyl and arylalkyl, saidprimary substituent optionally being substituted with secondarysubstituent selected from heteroaryl or heterocyclyl; and in which theother substitution at the alpha-carbon is hydrogen or alkyl; X_(aa2) isnaturally or nonnaturally occurring amino acid residue in which one ofthe substitutions at the alpha-carbon is an alkyl or cycloalkyl wherethe alkyl group may optionally form a ring with the nitrogen of X_(aa2);and wherein the other substitution at the alpha-carbon is hydrogen oralkyl; X_(aa3) is a naturally or nonnaturally occurring amino acidresidue in which one of the substitutions at the alpha-carbon isselected from the group consisting of a carboxyalkyl, bis-carboxyalkyl,sulfonylalkyl, heteroalkyl and mercaptoalkyl; and wherein the othersubstituion at the alpha-carbon is hydrogen or alkyl; X_(aa4) is anaturally or nonnaturally occurring amino acid residue in which thealpha-carbon is not substituted, or in which one of the substitutions atthe alpha-carbon is selected from the group consisting of aminoalkyl,carboxyalkyl heteroarylalkyl and heterocycylalkyl; X_(aa5) is anaturally or nonnaturally occurring amino acid residue in which one ofthe substitutions at the alpha-carbon is an alkyl or hydroxyalkyl, andin which the other substitution at the alpha-carbon is hydrogen oralkyl; X_(aa6) is a naturally or nonnaturally occurring amino acidresidue in which one of the substitutions at the alpha-carbon isselected from the group consisting of alkyl, aryl, heteroaryl,heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl andheteroarylalkyl group, and wherein the other substitution at thealpha-carbon is hydrogen or alkyl; X_(aa7) is a naturally ornonnaturally occurring amino acid residue in which one of thesubstitutions at the alpha-carbon is a hydroxylalkyl group; X_(aa8) is anaturally or nonnaturally occurring amino acid residue in which one ofthe substitutions at the alpha-carbon is selected from the groupconsisting of alkyl, hydroxylalkyl, heteroarylalkyl andcarboxamidoalkyl, and in which the other substitution at thealpha-carbon is hydrogen or alkyl; X_(aa9) is a naturally ornonnaturally occurring amino acid residue in which one of thesubstitutions at alpha-carbon is selected from the group consisting ofcarboxylalkyl, bis-carboxylalkyl, carboxylaryl, sulfonylalkyl,carboxylamidoalkyl and heteroarylalkyl; and wherein A is hydrogen, anamino acid or peptide containing from about 1 to about 5 amino acidresidues, an R group, an R—C(O) amide group, a carbamate group RO—C(O),a urea R₄R₅N—C(O), a sulfonamido R—SO₂ or a R₄R₅N—SO₂.
 9. The isolatedpolypeptide of claim 8 wherein X_(aa1) is an amino acid residue selectedfrom the group consisting of L-His, D-His, L-N-Methyl-His,D-N-Methyl-His, L-4-ThiazolylAla and D-4-ThiazolylAla; X_(aa2) is anamino acid residue selected from the group consisting of L-Ala, D-Ala,L-Pro, Gly, D-Ser, D-Asn, L-N-Methyl-Ala, D-N-Methyl-Ala, L-4-ThioPro,L-Pro(t-4-OH), L-2-Pip, L-2-Azt, Aib, S— or R-Iva and Acc₃; X_(aa3) isan amino acid residue selected from the group consisting of L-Glu,L-N-Methyl-Glu, L-Asp, D-Asp, L-His, L-Gla, L-Adp, L-Cys andL-4-ThiazolylAla; X_(aa4) is an amino acid residue selected from thegroup consisting of Gly, L-His, L-Lys and L-Asp; X_(aa5) is an aminoacid residue selected from the group consisting of L-Thr, D-Thr, L-Nle,L-Met, L-Nva and L-Aoc; X_(aa6) is an amino acid residue selected fromthe group consisting of L-Phe, L-Tyr, L-Tyr(Bzl), Tyr(3-NO₂), L-Nle,L-Trp, L-Phe(penta-Fluoro), D-Phe(penta-Fluoro), Phe(2-Fluoro),Phe(3-Fluoro), Phe(4-Fluoro), Phe(2,3-di-Fluoro), Phe(3,4-di-Fluoro),Phe(3,5-di-Fluoro), L-Phe(2,6-di-Fluoro), Phe(3,4,5-tri-Fluoro),Phe(2-Iodo), Phe(2-OH), Phe(2-OMethyl), Phe(3-OMethyl), Phe(3-Cyano),Phe(2-Chloro), Phe(2-NH₂), Phe(3-NH₂), Phe(4-NH₂), Phe(4-NO₂),Phe(4-Methyl), Phe(4-Allyl), Phe(n-butyl), Phe(4-Cyclohexyl),Phe(4-Cyclohexyloxy), Phe(4-Phenyloxy), 2-NaphthylAla, 2-PyridylAla,L-4-ThiazolylAla, L-2-Thi, L-α-Me-Phe, D-α-Me-Phe, L-α-Et-Phe,D-α-Et-Phe, L-α-Me-Phe(2-Fluoro), D-α-Me-Phe(2-Fluoro),L-α-Me-Phe(2,3-di-Fluoro), D-α-Me-Phe(2,3-di-Fluoro),L-α-Me-Phe(2,6-di-Fluoro), D-α-Me-Phe(2,6-di-Fluoro),L-α-Me-Phe(penta-Fluoro) and D-α-Me-Phe(penta-Fluoro); X_(aa7) is anamino acid residue selected from the group consisting of L-Thr, D-Thr,L-Ser and L-hSer; X_(aa8) is an amino acid residue selected from thegroup consisting of L-Ser, L-hSer, L-His, L-Asn and L-α-Me-Ser; andX_(aa9) is an amino acid residue selected from the group consisting ofL-Asp, L-Glu, L-Gla, L-Adp, L-Asn and L-His.
 10. The isolatedpolypeptide of claim 1 wherein Y is selected from the group consistng ofL-Bip, D-Bip, L-Bip(2-Me), D-Bip(2-Me), L-Bip(2′-Me), L-Bip(2-Et),D-Bip(2-Et), L-Bip(3-Et), L-Bip(4-Et), L-Bip(2-n-Propyl),L-Bip(2-n-Propyl, 4-OMe), L-Bip(2-n-Propyl, 2′-Me), L-Bip(3-Me),L-Bip(4-Me), L-Bip(2,3-di-Me), L-Bip(2,4-di-Me), L-Bip(2,6-di-Me),L-Bip(2,4-di-Et), L-Bip(2-Me, 2′-Me), L-Bip(2-Et, 2′-Me), L-Bip(2-Et,2′-Et), L-Bip(2-Me,4-OMe), L-Bip(2-Et,4-OMe), D-Bip(2-Et,4-OMe),L-Bip(3-OMe), L-Bip(4-OMe), L-Bip(2,4,6-tri-Me), L-Bip(2,3-di-OMe),L-Bip(2,4-di-OMe), L-Bip(2,5-di-OMe), L-Bip(3,4-di-OMe),L-Bip(2-Et,4,5-di-OMe), L-Bip(3,4-Methylene-di-oxy), L-Bip(2-Et,4,5-Methylene-di-oxy), L-Bip(2-CH₂OH, 4-OMe), L-Bip(2-Ac),L-Bip(3-NH—Ac), L-Bip(4-NH—Ac), L-Bip(2,3-di-Chloro),L-Bip(2,4-di-Chloro), L-Bip(2,5-di-Chloro), L-Bip(3,4-di-Chloro),L-Bip(4-Fluoro), L-Bip(3,4-di-Fluoro), L-Bip(2,5-di-Fluoro),L-Bip(3-n-Propyl), L-Bip(4-n-Propyl), L-Bip(2-iso-Propyl),L-Bip(3-iso-Propyl), L-Bip(4-iso-Propyl), L-Bip(4-tert-Butyl),L-Bip(3-Phenyl), L-Bip(2-Chloro), L-Bip(3-Chloro), L-Bip(2-Fluoro),L-Bip(3-Fluoro), L-Bip(2-CF₃), L-Bip(3-CF₃), L-Bip(4-CF₃), L-Bip(3-NO₂),L-Bip(3-OCF₃), L-Bip(4-OCF₃), L-Bip(2-OEt), L-Bip(3-OEt), L-Bip(4-OEt),L-Bip(4-SMe), L-Bip(2-OH), L-Bip(3-OH), L-Bip(4-OH), L-Bip(2-CH₂—COOH),L-Bip(3-CH₂—COOH), L-Bip(4-CH₂—COOH), L-Bip(2-CH₂—NH₂),L-Bip(3-CH₂—NH₂), L-Bip(4-CH₂—NH₂), L-Bip(2-CH₂—OH), L-Bip(3-CH₂—OH),L-Bip(4-CH₂—OH), L-Phe[4-(1-propargyl)], L-Phe[4-(1-propenyl)],L-Phe[4-n-Butyl], L-Phe[4-Cyclohexyl], Phe(4-Phenyloxy),L-Phe(penta-Fluoro), L-2-(9,10-Dihydrophenanthrenyl)-Ala,4-(2-Benzo(b)furan)-Phe, 4-(4-Dibenzofuran)-Phe, 4-(4-Phenoxathiin)-Phe,4-(2-Benzo(b)thiophene)-Phe, 4-(3-thiophene)-Phe, 4-(3-Quinoline)-Phe,4-(2-Naphthyl)-Phe, 4-(1-Naphthyl)-Phe,4-(4-(3,5-dimethylisoxazole))-Phe, 4-(2,4-dimethoxypyrimidine)-Phe,homophe, Tyr(Bzl), Phe(3,4-di-Chloro), Phe(4-Iodo), 2-Naphthyl-Ala,L-α-Me-Bip and D-α-Me-Bip; Z is selected from the group consisting ofL-Bip, D-Bip, L-Bip(2-Me), D-Bip(2-Me), L-Bip(2′-Me), L-Bip(2-Et),D-Bip(2-Et), L-Bip(3-Me), L-Bip(4-Me), L-Bip(3-OMe), L-Bip(4-OMe),L-Bip(4-Et), L-Bip(2-n-Propyl,2′-Me), L-Bip(2,4-di-Me), L-Bip(2-Me,2′-Me), L-Bip(2-Me,4-OMe), L-Bip(2-Et,4-OMe), D-Bip(2-Et,4-OMe),L-Bip(2,6-di-Me), L-Bip(2,4,6-tri-Me), L-Bip(2,3,4,5,-tetra-Me),L-Bip(3,4-di-OMe), L-Bip(2,5-di-OMe), L-Bip(3,4-Methylene-di-oxy),L-Bip(3-NH—Ac), L-Bip(2-iso-Propyl), L-Bip(4-iso-Propyl),L-Bip(2-Phenyl), L-Bip(4-Phenyl), L-Bip(2-Fluoro), L-Bip(4-CF₃),L-Bip(4-OCF₃), L-Bip(2-OEt), L-Bip(4-OEt), L-Bip(4-SMe),L-Bip(2-CH₂—COOH), D-Bip(2-CH₂—COOH), L-Bip(2′-CH₂—COOH),L-Bip(3-CH₂—COOH), L-Bip(4-CH₂—COOH), L-Bip(2-CH₂—NH₂),L-Bip(3-CH₂—NH₂), L-Bip(4-CH₂—NH₂), L-Bip(2-CH₂—OH), L-Bip(3-CH₂—OH),L-Bip(4-CH₂—OH), L-Phe(3-Phenyl), L-Phe[4-n-Butyl], L-Phe[4-Cyclohexyl],Phe(4-Phenyloxy), L-Phe(penta-Fluoro),L-2-(9,10-Dihydrophenanthrenyl)-Ala, 4-(3-Pyridyl)-Phe,4-(2-Naphthyl)-Phe, 4-(1-Naphthyl)-Phe, 2-Naphthyl-Ala, 2-Fluorenyl-Ala,L-α-Me-Bip, D-α-Me-Bip, L-Phe(4-NO₂) and L-Phe(4-Iodo); A is selectedfrom the group consisting of H, Acetyl, β-Ala, Ahx, Gly, Asp, Glu, Phe,Lys, Nva, Asn, Arg, Ser, Thr, Val, Trp, Tyr, Caprolactam, L-Bip,L-Ser(Bzl), 3-PyridylAla, Phe(4-Me), Phe(penta-Fluoro), 4-Methylbenzyl,4-Fluorobenzyl, n-propyl, n-hexyl, cyclohexylmethyl, 6-hydroxypentyl,2-Thienylmethyl, 3-Thienylmethyl, penta-Fluorobenzyl, 2-naphthylmethyl,4-biphenylmethyl, 9-Anthracenylmethyl, benzyl,(S)-(2-amino-3-phenyl)propyl, methyl, 2-aminoethyl and(S)-2-Aminopropyl; and B is selected from the group consisting of OH,NH₂, Trp-NH₂, 2-NaphthylAla-NH₂, Phe(penta-Fluoro)-NH₂, Ser(Bzl)-NH₂,Phe(4-NO₂)—NH₂, 3-PyridylAla-NH₂, Nva-NH₂, Lys-NH₂, Asp-NH₂, Ser-NH₂,His-NH₂, Tyr-NH₂, Phe-NH₂, L-Bip-NH₂, D-Ser-NH₂, Gly-OH, β-Ala-OH,GABA-OH and APA-OH.
 11. The isolated polypeptide of claim 1 wherein suchpolypeptide is a 10-mer to 15-mer and such polypeptide and binds to andactivates the GLP-1 receptor.
 12. An isolated polypeptide having asequence of Formula IA-X_(aa1)—X_(aa2)—X_(aa3)—X_(aa4)—X_(aa5)—X_(aa6)—X_(aa7)—X_(aa8)—X_(aa9)—Y-Z-B  I wherein, X_(aa1-9) is a naturally or nonnaturally occurring aminoacid residue; Y and Z are amino acid residues; wherein one of thesubstitutions at the alpha-carbon atoms of Y and Z may eachindependently be substituted with a primary substituent group selectedfrom the group consisting of hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, saidprimary substituent optionally being substituted with a secondarysubstituent selected from a cycloalkyl, heterocyclyl, aryl or heteroarylgroup; any of said primary or secondary substituents may further besubstituted with one or more of, hydrogen, alkyl, cycloalkyl, arylalkyl,aryl, heterocycle, heteroaryl, alkenyl, alkynyl, halo, hydroxy,mercapto, nitro, cyano, amino, acylamino, azido, guanidino, amidino,carboxyl, carboxamido, carboxamido alkyl, formyl, acyl, carboxyl alkyl,alkoxy, aryloxy, arylalkyloxy, heteroaryloxy, heterocycleoxy, acyloxy,mercapto, mercapto alkyl, mercaptoaryl, mercapto acyl, halo, cyano,nitro, azido, amino, guanidino alkyl, guanidino acyl, sulfonic,sulfonamido, alkyl sulfonyl, aryl sulfonyl or phosphonic group; wherein,the primary or secondary substitutents may optionally be bridged bycovalent bonds to form one or more fused cyclic or heterocyclic systemswith each other; wherein, the other substitution at the alpha-carbon ofY may be substituted with hydrogen, alkyl, aminoalkyl, hydroxyalkyl orcarboxyalkyl; wherein, the other substitution at the alpha-carbon of Zmay be substituted with hydrogen, alkyl, aminoalkyl, hydroxyalkyl orcarboxyalkyl; A and B are optionally present; wherein A is not present,and X_(aa1) is an R group, an R—C(O) (amide) group, a carbamate groupRO—C(O), a urea R₄R₅N—C(O) , a sulfonamido R—SO₂, or a R₄R₅N—SO₂;wherein R is selected from the group consisting of hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl,heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl, heteroaryloxyalkyland heteroarylalkoxyalkyl; wherein R₄ and R₅ are each independentlyselected from the group consisting of hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl,arylalkyl, aryloxyalkyl, heteroarylalkyl and heteroaryloxyalky; whereinB is present and B is OR₁, NR₁R₂, or an amino acid or peptide containingfrom 1 to 15 amino acid residues, terminating at the C-terminus as acarboxamide, substituted carboxamide, an ester, a free carboxylic acidor an amino-alcohol; wherein R₁ and R₂ are independently chosen fromhydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl,heteroarylalkyl or heteroaryloxyalkyl.
 13. The isolated polypeptide ofclaim 5 wherein the substitutions upon the alpha-carbon atoms of Y and Zare selected from the group consisting of heteroarylarylmethyl,arylheteroarylmethyl or biphenylmethyl forming biphenylalanine residues,any of which is also optionally substituted with one or more, hydrogen,alkyl, cycloalkyl, arylalkyl, aryl, heterocyclyl, heteroaryl, alkenyl,alkynyl, halo, hydroxy, mercapto, nitro, cyano, amino, acylamino, azido,guanidino, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl,acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy,heterocycleoxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl,mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl,guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl andphosphonic group.
 14. The isolated polypeptide of claim 12 wherein B isan amino acid or peptide containing 1 to about 10 amino acid residues.15. The isolated polypeptide of claim 14 wherein B is an amino acid orpeptide containing 1 to about 5 amino acid residues.
 16. The isolatedpolypeptide of claim 12 wherein X_(aa2) and X_(aa3) are N—H orN-alkylated amino acid residues.
 17. The isolated polypeptide of claim16 wherein X_(aa2) and X_(aa3) are N—H or N-methylated amino acidresidues.
 18. The isolated polypeptide of claim 12 wherein the othersubstitution at the alpha-carbon of Y is substituted with hydrogen,methyl or ethyl, and wherein the other substitution at the alpha-carbonof Z is substituted with hydrogen, methyl or ethyl.
 19. The isolatedpolypeptide of claim 12 wherein R, R₄ and R₅ are heteroarylalkyl orheterocycloalkyl, or R, R₄ and R₅ are cycloalkyl, cycloalkylalkyl,heterocycle, aryl, arylalkyl or aryloxyalkyl substituted with heteroarylor heterocycle.
 20. The isolated polypeptide of claim 12 wherein X_(aa2)is naturally or nonnaturally occurring amino acid residue in which oneof the substitutions at the alpha-carbon is an alkyl or cycloalkyl wherethe alkyl group may optionally form a ring with the nitrogen of X_(aa2),and wherein the other substitution at the alpha-carbon is hydrogen oralkyl; X_(aa3) is a naturally or nonnaturally occurring amino acidresidue in which one of the substitutions at the alpha-carbon isselected from the group consisting of a carboxyalkyl, bis-carboxyalkyl,sulfonylalkyl, heteroalkyl and mercaptoalkyl; and wherein the othersubstituion at the alpha-carbon is hydrogen or alkyl; X_(aa4) is anaturally or nonnaturally occurring amino acid residue in which thealpha-carbon is not substituted, or in which one of the substitutions atthe alpha-carbon is selected from the group consisting of aminoalkyl,carboxyalkyl heteroarylalkyl and heterocycylalkyl; X_(aa5) is anaturally or nonnaturally occurring amino acid residue in which one ofthe substitutions at the alpha-carbon is an alkyl or hydroxyalkyl, andin which the other substitution at the alpha-carbon is hydrogen oralkyl; X_(aa6) is a naturally or nonnaturally occurring amino acidresidue in which one of the substitutions at the alpha-carbon isselected from the group consisting of alkyl, aryl, heteroaryl,heterocycle, cycloalkylalkyl, heterocyclealkyl, arylalkyl andheteroarylalkyl, and wherein the other substitution at the alpha-carbonis hydrogen or alkyl; X_(aa7)is a naturally or nonnaturally occurringamino acid residue in which one of the substitutions at the alpha-carbonis a hydroxylalkyl group; X_(aa8) is a naturally or nonnaturallyoccurring amino acid residue in which one of the substitutions at thealpha-carbon is selected from the group consisting of alkyl,hydroxylalkyl, heteroarylalkyl and carboxamidoalkyl, and in which theother substitution at the alpha-carbon is hydrogen or alkyl; and X_(aa9)is a naturally or nonnaturally occurring amino acid residue in which oneof the substitutions at alpha-carbon is selected from the groupconsisting of carboxylalkyl, bis-carboxylalkyl, carboxylaryl,sulfonylalkyl, carboxylamidoalkyl and heteroarylalkyl.
 21. The isolatedpolypeptide of claim 20 wherein X_(aa2) is an amino acid residueselected from the group consisting of L-Ala, D-Ala, L-Pro, Gly, D-Ser,D-Asn, L-N-Methyl-Ala, D-N-Methyl-Ala, L-4-ThioPro, L-Pro(t-4-OH),L-2-Pip, L-2-Azt, Aib, S— or R-Iva and Acc₃; X_(aa3) is an amino acidresidue selected from the group consisting of L-Glu, L-N-Methyl-Glu,L-Asp, D-Asp, L-His, L-Gla, L-Adp, L-Cys and L-4-ThiazolylAla; X_(aa4)is an amino acid residue selected from the group consisting of Gly,L-His, L-Lys and L-Asp; X_(aa5) is an amino acid residue selected fromthe group consisting of L-Thr, D-Thr, L-Nle, L-Met, L-Nva and L-Aoc;X_(aa6) is an amino acid residue selected from the group consisting ofL-Phe, L-Tyr, L-Tyr(Bzl), Tyr(3-NO₂), L-Nle, L-Trp, L-Phe(penta-Fluoro),D-Phe(penta-Fluoro), Phe(2-Fluoro), Phe(3-Fluoro), Phe(4-Fluoro),Phe(2,3-di-Fluoro), Phe(3,4-di-Fluoro), Phe(3,5-di-Fluoro),L-Phe(2,6-di-Fluoro), Phe(3,4,5-tri-Fluoro), Phe(2-Iodo), Phe(2-OH),Phe(2-OMethyl), Phe(3-OMethyl), Phe(3-Cyano), Phe(2-Chloro), Phe(2-NH₂),Phe(3-NH₂), Phe(4-NH₂), Phe(4-NO₂), Phe(4-Methyl), Phe(4-Allyl),Phe(n-butyl), Phe(4-Cyclohexyl), Phe(4-Cyclohexyloxy), Phe(4-Phenyloxy),2-NaphthylAla, 2-PyridylAla, L-4-ThiazolylAla, L-2-Thi, L-α-Me-Phe,D-α-Me-Phe, L-α-Et-Phe, D-α-Et-Phe, L-α-Me-Phe(2-Fluoro),D-α-Me-Phe(2-Fluoro), L-α-Me-Phe(2,3-di-Fluoro),D-α-Me-Phe(2,3-di-Fluoro), L-α-Me-Phe(2,6-di-Fluoro),D-α-Me-Phe(2,6-di-Fluoro), L-α-Me-Phe(penta-Fluoro) andD-α-Me-Phe(penta-Fluoro); X_(aa7) is an amino acid residue selected fromthe group consisting of L-Thr, D-Thr, L-Ser and L-hSer; X_(aa8) is anamino acid residue selected from the group consisting of L-Ser, L-hSer,L-His, L-Asn and L-α-Me-Ser; and X_(aa9) is an amino acid residueselected from the group consisting of L-Asp, L-Glu, L-Gla, L-Adp, L-Asnand L-His.
 22. The isolated polypeptide of claim 12 wherein Y isselected from the group consisting of L-Bip, D-Bip, L-Bip(2-Me),D-Bip(2-Me), L-Bip(2′-Me), L-Bip(2-Et), D-Bip(2-Et), L-Bip(3-Et),L-Bip(4-Et), L-Bip(2-n-Propyl), L-Bip(2-n-Propyl, 4-OMe),L-Bip(2-n-Propyl,2′-Me), L-Bip(3-Me), L-Bip(4-Me), L-Bip(2,3-di-Me),L-Bip(2,4-di-Me), L-Bip(2,6-di-Me), L-Bip(2,4-di-Et), L-Bip(2-Me,2′-Me), L-Bip(2-Et, 2′-Me), L-Bip(2-Et, 2′-Et), L-Bip(2-Me,4-OMe),L-Bip(2-Et,4-OMe), D-Bip(2-Et,4-OMe), L-Bip(3-OMe), L-Bip(4-OMe),L-Bip(2,4,6-tri-Me), L-Bip(2,3-di-OMe), L-Bip(2,4-di-OMe),L-Bip(2,5-di-OMe), L-Bip(3,4-di-OMe), L-Bip(2-Et,4,5-di-OMe),L-Bip(3,4-Methylene-di-oxy), L-Bip(2-Et, 4,5-Methylene-di-oxy),L-Bip(2-CH₂OH, 4-OMe), L-Bip(2-Ac), L-Bip(3-NH—Ac), L-Bip(4-NH—Ac),L-Bip(2,3-di-Chloro), L-Bip(2,4-di-Chloro), L-Bip(2,5-di-Chloro),L-Bip(3,4-di-Chloro), L-Bip(4-Fluoro), L-Bip(3,4-di-Fluoro),L-Bip(2,5-di-Fluoro), L-Bip(3-n-Propyl), L-Bip(4-n-Propyl),L-Bip(2-iso-Propyl), L-Bip(3-iso-Propyl), L-Bip(4-iso-Propyl),L-Bip(4-tert-Butyl), L-Bip(3-Phenyl), L-Bip(2-Chloro), L-Bip(3-Chloro),L-Bip(2-Fluoro), L-Bip(3-Fluoro), L-Bip(2-CF₃), L-Bip(3-CF₃),L-Bip(4-CF₃), L-Bip(3-NO₂), L-Bip(3-OCF₃), L-Bip(4-OCF₃), L-Bip(2-OEt),L-Bip(3-OEt), L-Bip(4-OEt), L-Bip(4-SMe), L-Bip(2-OH), L-Bip(3-OH),L-Bip(4-OH), L-Bip(2-CH₂—COOH), L-Bip(3-CH₂—COOH), L-Bip(4-CH₂—COOH),L-Bip(2-CH₂—NH₂), L-Bip(3-CH₂—NH₂), L-Bip(4-CH₂—NH₂), L-Bip(2-CH₂—OH),L-Bip(3-CH₂—OH), L-Bip(4-CH₂—OH), L-Phe[4-(1-propargyl)],L-Phe[4-(1-propenyl)], L-Phe[4-n-Butyl], L-Phe[4-Cyclohexyl],Phe(4-Phenyloxy), L-Phe(penta-Fluoro),L-2-(9,10-Dihydrophenanthrenyl)-Ala, 4-(2-Benzo(b)furan)-Phe,4-(4-Dibenzofuran)-Phe, 4-(4-Phenoxathiin)-Phe,4-(2-Benzo(b)thiophene)-Phe, 4-(3-thiophene)-Phe, 4-(3-Quinoline)-Phe,4-(2-Naphthyl)-Phe, 4-(1-Naphthyl)-Phe,4-(4-(3,5-dimethylisoxazole))-Phe, 4-(2,4-dimethoxypyrimidine)-Phe,homoPhe, Tyr(Bzl), Phe(3,4-di-Chloro), Phe(4-Iodo), 2-Naphthyl-Ala,L-α-Me-Bip and D-α-Me-Bip; Z is selected from the group consisting ofL-Bip, D-Bip, L-Bip(2-Me), D-Bip(2-Me), L-Bip(2′-Me), L-Bip(2-Et),D-Bip(2-Et), L-Bip(3-Me), L-Bip(4-Me), L-Bip(3-OMe), L-Bip(4-OMe),L-Bip(4-Et), L-Bip(2-n-Propyl,2′-Me), L-Bip(2,4-di-Me), L-Bip(2-Me,2′-Me), L-Bip(2-Me,4-OMe), L-Bip(2-Et,4-OMe), D-Bip(2-Et,4-OMe),L-Bip(2,6-di-Me), L-Bip(2,4,6-tri-Me), L-Bip(2,3,4,5,-tetra-Me),L-Bip(3,4-di-OMe), L-Bip(2,5-di-OMe), L-Bip(3,4-Methylene-di-oxy),L-Bip(3-NH—Ac), L-Bip(2-iso-Propyl), L-Bip(4-iso-Propyl),L-Bip(2-Phenyl), L-Bip(4-Phenyl), L-Bip(2-Fluoro), L-Bip(4-CF₃),L-Bip(4-OCF₃), L-Bip(2-OEt), L-Bip(4-OEt), L-Bip(4-SMe),L-Bip(2-CH₂—COOH), D-Bip(2-CH₂—COOH), L-Bip(2′-CH₂—COOH),L-Bip(3-CH₂—COOH), L-Bip(4-CH₂—COOH), L-Bip(2-CH₂—NH₂),L-Bip(3-CH₂—NH₂), L-Bip(4-CH₂—NH₂), L-Bip(2-CH₂—OH), L-Bip(3-CH₂—OH),L-Bip(4-CH₂—OH), L-Phe(3-Phenyl), L-Phe[4-n-Butyl], L-Phe[4-Cyclohexyl],Phe(4-Phenyloxy), L-Phe(penta-Fluoro),L-2-(9,10-Dihydrophenanthrenyl)-Ala, 4-(3-Pyridyl)-Phe,4-(2-Naphthyl)-Phe, 4-(1-Naphthyl)-Phe, 2-Naphthyl-Ala, 2-Fluorenyl-Ala,L-α-Me-Bip, D-α-Me-Bip, L-Phe(4-NO₂) and L-Phe(4-Iodo); and B isselected from the group consisting of OH, NH₂, Trp-NH₂,2-NaphthylAla-NH₂, Phe(penta-Fluoro)-NH₂, Ser(Bzl)-NH₂, Phe(4-NO₂)—NH₂,3-PyridylAla-NH₂, Nva-NH₂, Lys-NH₂, Asp-NH₂, Ser-NH₂, His-NH₂, Tyr-NH₂,Phe-NH₂, L-Bip-NH₂, D-Ser-NH₂, Gly-OH, β-Ala-OH, GABA-OH and APA-OH. 23.The isolated polypeptide of claim 12 wherein such polypeptide is a10-mer to 15-mer and such polypeptide and binds to and activates theGLP-1 receptor.
 24. An isolated polypeptide having a sequence of FormulaIA-X_(aa1)—X_(aa2)—X_(aa3)—X_(aa4)—X_(aa5)—X_(aa6)—X_(aa7)—X_(aa8)—X_(aa9)—Y-Z-B  I wherein, X_(aa1-9) is a naturally or nonnaturally occurring aminoacid residue; Y is an amino acid residue; wherein one of thesubstitutions at the alpha-carbon atom of Y may independently besubstituted with a primary substituent group selected from the groupconsisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,heterocyclylalkyl, arylalkyl and heteroarylalkyl, said primarysubstituent optionally being substituted with a secondary substituentselected from a cycloalkyl, heterocyclyl, aryl or heteroaryl group; anyof said primary or secondary substituents may further be substitutedwith one or more of, hydrogen, alkyl, cycloalkyl, arylalkyl, aryl,heterocyclyl, heteroaryl, alkenyl, alkynyl, halo, hydroxy, mercapto,nitro, cyano, amino, acylamino, azido, guanidino, amidino, carboxyl,carboxamido, carboxamido alkyl, formyl, acyl, carboxyl alkyl, alkoxy,aryloxy, arylalkyloxy, heteroaryloxy, heterocyclyloxy, acyloxy,mercapto, mercapto alkyl, mercaptoaryl, mercapto acyl, halo, cyano,nitro, azido, amino, guanidino alkyl, guanidino acyl, sulfonic,sulfonamido, alkyl sulfonyl, aryl sulfonyl or phosphonic group; wherein,the primary or secondary substitutents may optionally be bridged bycovalent bonds to form one or more fused cyclic or heterocyclic systemswith each other; wherein, the other substitution at the alpha-carbon ofY may be substituted with hydrogen, alkyl, aminoalkyl, hydroxyalkyl orcarboxyalkyl; A and B are optionally present; wherein A is present and Ais hydrogen, an amino acid or peptide containing from about 1 to about15 amino acid residues, an R group, an R—C(O) (amide) group, a carbamategroup RO—C(O), a urea R₄R₅N—C (O), a sulfonamido R—SO₂ or a R₄R₅N—SO₂;wherein R is selected from the group consisting of hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl,heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl andheteroaryloxyalkyl; wherein R₄ and R₅ are each independently selectedfrom the group consisting of hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, heteroaryl,arylalkyl, aryloxyalkyl, heteroarylalkyl and heteroaryloxyalky; whereinthe alpha-amino group of X_(aa1) is substituted with a hydrogen or analkyl group, said alkyl group may optionally form a ring with A; whereinB is not present and Z is OR₁, NR₁R₂ or an amino-alcohol; and wherein R1and R₂ are independently chosen from hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, heteroaryl,arylalkyl, aryloxyalkyl, heteroarylalkyl or heteroaryloxyalkyl.
 25. Theisolated polypeptide of claim 24 wherein the substitutions upon thealpha-carbon atoms of Y are selected from the group consisting ofheteroarylarylmethyl, arylheteroarylmethyl or biphenylmethyl formingbiphenylalanine residues, any of which is also optionally substitutedwith one or more, hydrogen, alkyl, cycloalkyl, arylalkyl, aryl,heterocyclyl, heteroaryl, alkenyl, alkynyl, halo, hydroxy, mercapto,nitro, cyano, amino, acylamino, azido, guanidino, amidino, carboxyl,carboxamido, carboxamido alkyl, formyl, acyl, carboxyl alkyl, alkoxy,aryloxy, arylalkyloxy, heteroaryloxy, heterocycleoxy, acyloxy, mercapto,mercapto alkyl, mercaptoaryl, mercapto acyl, halo, cyano, nitro, azido,amino, guanidino alkyl, guanidino acyl, sulfonic, sulfonamido, alkylsulfonyl, aryl sulfonyl and phosphonic group.
 26. The isolatedpolypeptide of claim 24 wherein B is an amino acid or peptide containing1 to about 10 amino acid residues.
 27. The isolated polypeptide of claim26 wherein B is an amino acid or peptide containing 1 to about 5 aminoacid residues.
 28. The isolated polypeptide of claim 24 wherein X_(aa1),X_(aa2) and X_(aa3) are N—H or N-alkylated amino acid residues.
 29. Theisolated polypeptide of claim 28 wherein X_(aa1), X_(aa2) and X_(aa3)are N—H or N-methylated amino acid residues.
 30. The isolatedpolypeptide of claim 24 wherein the other substitution at thealpha-carbon of Y is substituted with hydrogen, methyl or ethyl.
 31. Theisolated polypeptide of claim 24 wherein X_(aa1) is naturally ornonnaturally occurring amino acid residue in which one of thesubstitutions at the alpha-carbon is a primary substituent selected fromthe group consisting of heterocyclylalkyl, heteroaryl, heteroarylkalkyl,and arylalkyl, said primary substituent optionally being substitutedwith secondary substituent selected from heteroaryl or heterocyclyl, andwherein the other substitution at the alpha-carbon is hydrogen or alkyl;X_(aa2) is naturally or nonnaturally occurring amino acid residue inwhich one of the substitutions at the alpha-carbon is an alkyl orcycloalkyl where the alkyl group may optionally form a ring with thenitrogen of X_(aa2), and wherein the other substitution at thealpha-carbon is hydrogen or alkyl; X_(aa3) is a naturally ornonnaturally occurring amino acid residue in which one of thesubstitutions at the alpha-carbon is selected from the group consistingof a carboxyalkyl, bis-carboxyalkyl, sulfonylalkyl, heteroalkyl andmercaptoalkyl, and wherein the other substituion at the alpha-carbon ishydrogen or alkyl; X_(aa4) is a naturally or nonnaturally occurringamino acid residue in which the alpha-carbon is not substituted, or inwhich one of the substitutions at the alpha-carbon is selected from thegroup consisting of aminoalkyl, carboxyalkyl heteroarylalkyl andheterocycylalkyl; X_(aa5) is a naturally or nonnaturally occurring aminoacid residue in which one of the substitutions at the alpha-carbon is analkyl or hydroxyalkyl, and wherein the other substitution at thealpha-carbon is hydrogen or alkyl; X_(aa6) is a naturally ornonnaturally occurring amino acid residue in which one of thesubstitutions at the alpha-carbon is selected from the group consistingof alkyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl,heterocyclealkyl, arylalkyl and heteroarylalkyl group, and wherein theother substitution at the alpha-carbon is hydrogen or alkyl; X_(aa7) isis a naturally or nonnaturally occurring amino acid residue in which oneof the substitutions at the alpha-carbon is a hydroxylalkyl group;X_(aa8) is a naturally or nonnaturally occurring amino acid residue inwhich one of the substitutions at the alpha-carbon is selected from thegroup consisting of alkyl, hydroxylalkyl, heteroarylalkyl andcarboxamidoalkyl, and wherein the other substitution at the alpha-carbonis hydrogen or alkyl; X_(aa9) is a naturally or nonnaturally occurringamino acid residue in which one of the substitutions at alpha-carbon isselected from the group consisting of carboxylalkyl, bis-carboxylalkyl,carboxylaryl, sulfonylalkyl, carboxylamidoalkyl and heteroarylalkyl; andwherein A is hydrogen, an amino acid or peptide containing from about 1to about 5 amino acid residues, an R group, an R—C(O) (amide) group, acarbamate group RO—C(O), a urea R₄R₅N—C(O), a sulfonamido R—SO₂ or aR₄R₅N—SO₂.
 32. The isolated polypeptide of claim 31 wherein, X_(aa1) isan amino acid residue selected from the group consisting of L-His,D-His, L-N-Methyl-His, D-N-Methyl-His, L-4-ThiazolylAla andD-4-ThiazolylAla; X_(aa2) is an amino acid residue selected from thegroup consisting of L-Ala, D-Ala, L-Pro, Gly, D-Ser, D-Asn,L-N-Methyl-Ala, D-N-Methyl-Ala, L-4-ThioPro, L-Pro(t-4-OH), L-2-Pip,L-2-Azt, Aib, S— or R-Iva and Acc₃; X_(aa3) is an amino acid residueselected from the group consisting of L-Glu, L-N-Methyl-Glu, L-Asp,D-Asp, L-His, L-Gla, L-Adp, L-Cys and L-4-ThiazolylAla; X_(aa4) is anamino acid residue selected from the group consisting of Gly, L-His,L-Lys and L-Asp; X_(aa5) is an amino acid residue selected from thegroup consisting of L-Thr, D-Thr, L-Nle, L-Met, L-Nva and L-Aoc; X_(aa6)is an amino acid residue selected from the group consisting of L-Phe,L-Tyr, L-Tyr(Bzl), Tyr(3-NO₂), L-Nle, L-Trp, L-Phe(penta-Fluoro),D-Phe(penta-Fluoro), Phe(2-Fluoro), Phe(3-Fluoro), Phe(4-Fluoro),Phe(2,3-di-Fluoro), Phe(3,4-di-Fluoro), Phe(3,5-di-Fluoro),L-Phe(2,6-di-Fluoro), Phe(3,4,5-tri-Fluoro), Phe(2-Iodo), Phe(2-OH),Phe(2-OMethyl), Phe(3-OMethyl), Phe(3-Cyano), Phe(2-Chloro), Phe(2-NH₂),Phe(3-NH₂), Phe(4-NH₂), Phe(4-NO₂), Phe(4-Methyl), Phe(4-Allyl),Phe(n-butyl), Phe(4-Cyclohexyl), Phe(4-Cyclohexyloxy), Phe(4-Phenyloxy),2-NaphthylAla, 2-PyridylAla, L-4-ThiazolylAla, L-2-Thi, L-α-Me-Phe,D-α-Me-Phe, L-α-Et-Phe, D-α-Et-Phe, L-α-Me-Phe(2-Fluoro),D-α-Me-Phe(2-Fluoro), L-α-Me-Phe(2,3-di-Fluoro),D-α-Me-Phe(2,3-di-Fluoro), L-α-Me-Phe(2,6-di-Fluoro),D-α-Me-Phe(2,6-di-Fluoro), L-α-Me-Phe(penta-Fluoro) andD-α-Me-Phe(penta-Fluoro); X_(aa7) is an amino acid residue selected fromthe group consisting of L-Thr, D-Thr, L-Ser and L-hSer; X_(aa8) is anamino acid residue selected from the group consisting of L-Ser, L-hSer,L-His, L-Asn and L-α-Me-Ser; and X_(aa9) is an amino acid residueselected from the group consisting of L-Asp, L-Glu, L-Gla, L-Adp, L-Asnand L-His.
 33. The isolated polypeptide of claim 24 wherein Y isselected from the group consisting of L-Bip, D-Bip, L-Bip(2-Me),D-Bip(2-Me), L-Bip(2′-Me), L-Bip(2-Et), D-Bip(2-Et), L-Bip(3-Et),L-Bip(4-Et), L-Bip(2-n-Propyl), L-Bip(2-n-Propyl, 4-OMe),L-Bip(2-n-Propyl,2′-Me), L-Bip(3-Me), L-Bip(4-Me), L-Bip(2,3-di-Me),L-Bip(2,4-di-Me), L-Bip(2,6-di-Me), L-Bip(2,4-di-Et), L-Bip(2-Me,2′-Me), L-Bip(2-Et, 2′-Me), L-Bip(2-Et, 2′-Et), L-Bip(2-Me,4-OMe),L-Bip(2-Et,4-OMe), D-Bip(2-Et,4-OMe), L-Bip(3-OMe), L-Bip(4-OMe),L-Bip(2,4,6-tri-Me), L-Bip(2,3-di-OMe), L-Bip(2,4-di-OMe),L-Bip(2,5-di-OMe), L-Bip(3,4-di-OMe), L-Bip(2-Et,4,5-di-OMe),L-Bip(3,4-Methylene-di-oxy), L-Bip(2-Et, 4,5-Methylene-di-oxy),L-Bip(2-CH₂OH, 4-OMe), L-Bip(2-Ac), L-Bip(3-NH—Ac), L-Bip(4-NH—Ac),L-Bip(2,3-di-Chloro), L-Bip(2,4-di-Chloro), L-Bip(2,5-di-Chloro),L-Bip(3,4-di-Chloro), L-Bip(4-Fluoro), L-Bip(3,4-di-Fluoro),L-Bip(2,5-di-Fluoro), L-Bip(3-n-Propyl), L-Bip(4-n-Propyl),L-Bip(2-iso-Propyl), L-Bip(3-iso-Propyl), L-Bip(4-iso-Propyl),L-Bip(4-tert-Butyl), L-Bip(3-Phenyl), L-Bip(2-Chloro), L-Bip(3-Chloro),L-Bip(2-Fluoro), L-Bip(3-Fluoro), L-Bip(2-CF₃), L-Bip(3-CF₃),L-Bip(4-CF₃), L-Bip(3-NO₂), L-Bip(3-OCF₃), L-Bip(4-OCF₃), L-Bip(2-OEt),L-Bip(3-OEt), L-Bip(4-OEt), L-Bip(4-SMe), L-Bip(2-OH), L-Bip(3-OH),L-Bip(4-OH), L-Bip(2-CH₂—COOH), L-Bip(3-CH₂—COOH), L-Bip(4-CH₂—COOH),L-Bip(2-CH₂—NH₂), L-Bip(3-CH₂—NH₂), L-Bip(4-CH₂—NH₂), L-Bip(2-CH₂—OH),L-Bip(3-CH₂—OH), L-Bip(4-CH₂—OH), L-Phe[4-(1-propargyl)],L-Phe[4-(1-propenyl)], L-Phe[4-n-Butyl], L-Phe[4-Cyclohexyl],Phe(4-Phenyloxy), L-Phe(penta-Fluoro),L-2-(9,10-Dihydrophenanthrenyl)-Ala, 4-(2-Benzo(b)furan)-Phe,4-(4-Dibenzofuran)-Phe, 4-(4-Phenoxathiin)-Phe,4-(2-Benzo(b)thiophene)-Phe, 4-(3-thiophene)-Phe, 4-(3-Quinoline)-Phe,4-(2-Naphthyl)-Phe, 4-(1-Naphthyl)-Phe,4-(4-(3,5-dimethylisoxazole))-Phe, 4-(2,4-dimethoxypyrimidine)-Phe,homoPhe, Tyr(Bzl), Phe(3,4-di-Chloro), Phe(4-Iodo), 2-Naphthyl-Ala,L-α-Me-Bip and D-α-Me-Bip; and A is selected from the group consistingof H, Acetyl, β-Ala, Ahx, Gly, Asp, Glu, Phe, Lys, Nva, Asn, Arg, Ser,Thr, Val, Trp, Tyr, Caprolactam, L-Bip, L-Ser(Bzl), 3-PyridylAla,Phe(4-Me), Phe(penta-Fluoro), 4-Methylbenzyl, 4-Fluorobenzyl, n-propyl,n-hexyl, cyclohexylmethyl, 6-hydroxypentyl, 2-Thienylmethyl,3-Thienylmethyl, penta-Fluorobenzyl, 2-naphthylmethyl, 4-biphenylmethyl,9-Anthracenylmethyl, benzyl, (S)-(2-amino-3-phenyl)propyl, methyl,2-aminoethyl and (S)-2-Aminopropyl.
 34. The present invention alsoprovides an isolated polypeptide of claim 24 wherein such polypeptide isa 10-mer to 15-mer and such polypeptide and binds to and activates theGLP-1 receptor.
 35. An isolated polypeptide having a sequence of FormulaIA-X_(aa1)—X_(aa2)—X_(aa3)—X_(aa4)—X_(aa5)—X_(aa6)—X_(aa7)—X_(aa8)—X_(aa9)—Y-Z-B  I wherein, X_(aa1-9) is a naturally or nonnaturally occurring aminoacid residue; Y is an amino acid residue; wherein one of thesubstitutions at the alpha-carbon atom of Y may each independently besubstituted with a primary substituent group selected from the groupconsisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,heterocyclylalkyl, arylalkyl and heteroarylalkyl, said primarysubstituent optionally being substituted with a primary or secondarysubstituent selected from a cycloalkyl, heterocycle, aryl or heteroarylgroup; any of said secondary substituents may further be substitutedwith one or more of, hydrogen, alkyl, cycloalkyl, arylalkyl, aryl,heterocycle, heteroaryl, alkenyl, alkynyl, halo, hydroxy, mercapto,nitro, cyano, amino, acylamino, azido, guanidino, amidino, carboxyl,carboxamido, carboxamido alkyl, formyl, acyl, carboxyl alkyl, alkoxy,aryloxy, arylalkyloxy, heteroaryloxy, heterocycleoxy, acyloxy, mercapto,mercapto alkyl, mercaptoaryl, mercapto acyl, halo, cyano, nitro, azido,amino, guanidino alkyl, guanidino acyl, sulfonic, sulfonamido, alkylsulfonyl, aryl sulfonyl or phosphonic group; wherein, the primary orsecondary substitutents may optionally be bridged by covalent bonds toform one or more fused cyclic or heterocyclic systems with each other;wherein, the other substitution at the alpha-carbon of Y may besubstituted with hydrogen, alkyl, aminoalkyl, hydroxyalkyl orcarboxyalkyl; A and B are optionally present; wherein A is not present,and X_(aa1) is an R group, an R—C(O) (amide) group, a carbamate groupRO—C(O), a urea R₄R₅N—C(O), a sulfonamido R—SO₂ or a R₄R₅N—SO₂; whereinR is selected from the group consisting of hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, heteroaryl,arylalkyl, aryloxyalkyl, heteroarylalkyl, heteroaryloxyalkyl andheteroarylalkoxyalkyl; wherein R₄ and R₅ are each independently selectedfrom the group consisting of hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, heteroaryl,arylalkyl, aryloxyalkyl, heteroarylalkyl and heteroaryloxyalky; whereinB is not present and Z is OR₁, NR₁R₂ or an amino-alcohol; and wherein R₁and R₂ are independently chosen from hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, heteroaryl,arylalkyl, aryloxyalkyl, heteroarylalkyl or heteroaryloxyalkyl.
 36. Theisolated polypeptide of claim 35 wherein the substitutions upon thealpha-carbon atoms of Y are selected from the group consisting ofheteroarylarylmethyl, arylheteroarylmethyl or biphenylmethyl formingbiphenylalanine residues, any of which is also optionally substitutedwith one or more, hydrogen, alkyl, cycloalkyl, arylalkyl, aryl,heterocycle, heteroaryl, alkenyl, alkynyl, halo, hydroxy, mercapto,nitro, cyano, amino, acylamino, azido, guanidino, amidino, carboxyl,carboxamido, carboxamido alkyl, formyl, acyl, carboxyl alkyl, alkoxy,aryloxy, arylalkyloxy, heteroaryloxy, heterocycleoxy, acyloxy, mercapto,mercapto alkyl, mercaptoaryl, mercapto acyl, halo, cyano, nitro, azido,amino, guanidino alkyl, guanidino acyl, sulfonic, sulfonamido, alkylsulfonyl, aryl sulfonyl and phosphonic group.
 37. The isolatedpolypeptide of claim 35 wherein X_(aa2) and X_(aa3) are N—H orN-alkylated amino acids residues.
 38. The isolated polypeptide of claim37 wherein X_(aa2) and X_(aa3) are N—H or N-methylated amino acidresidues.
 39. The isolated polypeptide of claim 35 wherein the othersubstitution at the alpha-carbon of Y is substituted with methyl orethyl.
 40. The isolated polypeptide of claim 35 wherein R, R₄ and R₅ areheteroarylalkyl or heterocycloalkyl, or R, R₄ and R₅ are cycloalkyl,cycloalkylalkyl, heterocycle, aryl, arylalkyl or aryloxyalkylsubstituted with heteroaryl or heterocycle.
 41. The isolated polypeptideof claim 35 wherein X_(aa2) is naturally or nonnaturally occurring aminoacid residue in which one of the substitutions at the alpha-carbon is analkyl or cycloalkyl where the alkyl group may optionally form a ringwith the nitrogen of X_(aa2,) and wherein the other substitution at thealpha-carbon is hydrogen or alkyl; X_(aa3) is a naturally ornonnaturally occurring amino acid residue in which one of thesubstitutions at the alpha-carbon is selected from the group consistingof a carboxyalkyl, bis-carboxyalkyl, sulfonylalkyl, heteroalkyl andmercaptoalkyl, and wherein the other substituion at the alpha-carbon ishydrogen or alkyl; X_(aa4) is a naturally or nonnaturally occurringamino acid residue in which the alpha-carbon is not substituted, or inwhich one of the substitutions at the alpha-carbon is selected from thegroup consisting of aminoalkyl, carboxyalkyl heteroarylalkyl andheterocycylalkyl; X_(aa5) is a naturally or nonnaturally occurring aminoacid residue in which one of the substitutions at the alpha-carbon is analkyl or hydroxyalkyl, and wherein the other substitution at thealpha-carbon is hydrogen or alkyl; X_(aa6) is a naturally ornonnaturally occurring amino acid residue in which one of thesubstitutions at the alpha-carbon is selected from the group consistingof alkyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl,heterocyclealkyl, arylalkyl and heteroarylalkyl, and wherein the othersubstitution at the alpha-carbon is hydrogen or alkyl; X_(aa7) is is anaturally or nonnaturally occurring amino acid residue in which one ofthe substitutions at the alpha-carbon is a hydroxylalkyl group; X_(aa8)is a naturally or nonnaturally occurring amino acid residue in which oneof the substitutions at the alpha-carbon is selected from the groupconsisting of alkyl, hydroxylalkyl, heteroarylalkyl andcarboxamidoalkyl, and wherein the other substitution at the alpha-carbonis hydrogen or alkyl; and Xaa9 is a naturally or nonnaturally occurringamino acid residue in which one of the substitutions at alpha-carbon isselected from the group consisting of carboxylalkyl, bis-carboxylalkyl,carboxylaryl, sulfonylalkyl, carboxylamidoalkyl and heteroarylalkyl. 42.The isolated polypeptide of claim 41 wherein X_(aa2) is an amino acidresidue selected from the group consisting of L-Ala, D-Ala, L-Pro, Gly,D-Ser, D-Asn, L-N-Methyl-Ala, D-N-Methyl-Ala, L-4-ThioPro,L-Pro(t-4-OH), L-2-Pip, L-2-Azt, Aib, S— or R-Iva and Acc₃; X_(aa3) isan amino acid residue selected from the group consisting of L-Glu,L-N-Methyl-Glu, L-Asp, D-Asp, L-His, L-Gla, L-Adp, L-Cys andL-4-ThiazolylAla; X_(aa4) is an amino acid residue selected from thegroup consisting of Gly, L-His, L-Lys and L-Asp; X_(aa5) is an aminoacid residue selected from the group consisting of L-Thr, D-Thr, L-Nle,L-Met, L-Nva and L-Aoc; X_(aa6) is an amino acid residue selected fromthe group consisting of L-Phe, L-Tyr, L-Tyr(Bzl), Tyr(3-NO₂), L-Nle,L-Trp, L-Phe(penta-Fluoro), D-Phe(penta-Fluoro), Phe(2-Fluoro),Phe(3-Fluoro), Phe(4-Fluoro), Phe(2,3-di-Fluoro), Phe(3,4-di-Fluoro),Phe(3,5-di-Fluoro), L-Phe(2,6-di-Fluoro), Phe(3,4,5-tri-Fluoro),Phe(2-Iodo), Phe(2-OH), Phe(2-OMethyl), Phe(3-OMethyl), Phe(3-Cyano),Phe(2-Chloro), Phe(2-NH₂), Phe(3-NH₂), Phe(4-NH₂), Phe(4-NO₂),Phe(4-Methyl), Phe(4-Allyl), Phe(n-butyl), Phe(4-Cyclohexyl),Phe(4-Cyclohexyloxy), Phe(4-Phenyloxy), 2-NaphthylAla, 2-PyridylAla,L-4-ThiazolylAla, L-2-Thi, L-α-Me-Phe, D-α-Me-Phe, L-α-Et-Phe,D-α-Et-Phe, L-α-Me-Phe(2-Fluoro), D-α-Me-Phe(2-Fluoro),L-α-Me-Phe(2,3-di-Fluoro), D-α-Me-Phe(2,3-di-Fluoro),L-α-Me-Phe(2,6-di-Fluoro), D-α-Me-Phe(2,6-di-Fluoro),L-α-Me-Phe(penta-Fluoro) and D-α-Me-Phe(penta-Fluoro); X_(aa7) is anamino acid residue selected from the group consisting of L-Thr, D-Thr,L-Ser and L-hSer; X_(aa8) is an amino acid residue selected from thegroup consisting of L-Ser, L-hSer, L-His, L-Asn and L-α-Me-Ser; andX_(aa9) is an amino acid residue selected from the group consisting ofL-Asp, L-Glu, L-Gla, L-Adp, L-Asn and L-His.
 43. The isolatedpolypeptide of claim 35 wherein Y is selected from the group consistngof L-Bip, D-Bip, L-Bip(2-Me), D-Bip(2-Me), L-Bip(2′-Me), L-Bip(2-Et),D-Bip(2-Et), L-Bip(3-Et), L-Bip(4-Et), L-Bip(2-n-Propyl),L-Bip(2-n-Propyl, 4-OMe), L-Bip(2-n-Propyl,2′-Me), L-Bip(3-Me),L-Bip(4-Me), L-Bip(2,3-di-Me), L-Bip(2,4-di-Me), L-Bip(2,6-di-Me),L-Bip(2,4-di-Et), L-Bip(2-Me, 2′-Me), L-Bip(2-Et, 2′-Me), L-Bip(2-Et,2′-Et), L-Bip(2-Me,4-OMe), L-Bip(2-Et,4-OMe), D-Bip(2-Et,4-OMe),L-Bip(3-OMe), L-Bip(4-OMe), L-Bip(2,4,6-tri-Me), L-Bip(2,3-di-OMe),L-Bip(2,4-di-OMe), L-Bip(2,5-di-OMe), L-Bip(3,4-di-OMe),L-Bip(2-Et,4,5-di-OMe), L-Bip(3,4-Methylene-di-oxy), L-Bip(2-Et,4,5-Methylene-di-oxy), L-Bip(2-CH₂OH, 4-OMe), L-Bip(2-Ac),L-Bip(3-NH—Ac), L-Bip(4-NH—Ac), L-Bip(2,3-di-Chloro),L-Bip(2,4-di-Chloro), L-Bip(2,5-di-Chloro), L-Bip(3,4-di-Chloro),L-Bip(4-Fluoro), L-Bip(3,4-di-Fluoro), L-Bip(2,5-di-Fluoro),L-Bip(3-n-Propyl), L-Bip(4-n-Propyl), L-Bip(2-iso-Propyl),L-Bip(3-iso-Propyl), L-Bip(4-iso-Propyl), L-Bip(4-tert-Butyl),L-Bip(3-Phenyl), L-Bip(2-Chloro), L-Bip(3-Chloro), L-Bip(2-Fluoro),L-Bip(3-Fluoro), L-Bip(2-CF₃) , L-Bip(3-CF₃), L-Bip(4-CF₃),L-Bip(3-NO₂), L-Bip(3-OCF₃), L-Bip(4-OCF₃), L-Bip(2-OEt), L-Bip(3-OEt),L-Bip(4-OEt), L-Bip(4-SMe), L-Bip(2-OH), L-Bip(3-OH), L-Bip (4-OH),L-Bip(2-CH₂—COOH), L-Bip(3-CH₂—COOH), L-Bip(4-CH₂—COOH),L-Bip(2-CH₂—NH₂), L-Bip(3-CH₂—NH₂), L-Bip(4-CH₂—NH₂), L-Bip(2-CH₂—OH),L-Bip(3-CH₂—OH), L-Bip(4-CH₂—OH), L-Phe[4-(1-propargyl)],L-Phe[4-(1-propenyl)], L-Phe[4-n-Butyl], L-Phe[4-Cyclohexyl],Phe(4-Phenyloxy), L-Phe(penta-Fluoro),L-2-(9,10-Dihydrophenanthrenyl)-Ala, 4-(2-Benzo(b)furan)-Phe,4-(4-Dibenzofuran)-Phe, 4-(4-Phenoxathiin)-Phe,4-(2-Benzo(b)thiophene)-Phe, 4-(3-thiophene)-Phe, 4-(3-Quinoline)-Phe,4-(2-Naphthyl)-Phe, 4-(1-Naphthyl)-Phe,4-(4-(3,5-dimethylisoxazole))-Phe, 4-(2,4-dimethoxypyrimidine)-Phe,homoPhe, Tyr(Bzl), Phe(3,4-di-Chloro), Phe(4-Iodo), 2-Naphthyl-Ala,L-α-Me-Bip and D-α-Me-Bip.
 44. The isolated polypeptide of claim 35wherein such polypeptide is a 10-mer to 15-mer and such polypeptide andbinds to and activates the GLP-1 receptor.
 45. A method of making apolypeptide recognized by the family of B G-protein coupled receptorswherein the polypeptide mimics the activity of a polypeptide receptoragonist, said polypeptide having the formula

the method comprising replacing an address sequence of the polypeptidereceptor agonist with Y and Z, wherein Y and Z are are amino acidresidues; wherein one of the substitutions at the alpha-carbon atoms ofY and Z may each independently be substituted with a primary substituentgroup selected from the group consisting of hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl,heterocyclyl said primary substituent optionally being substituted witha secondary substituent selected from a cycloalkyl, heterocyclyl, arylor heteroaryl group; any of said primary or secondary substituents mayfurther be substituted with one or more of, hydrogen, alkyl, cycloalkyl,arylalkyl, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl, halo,hydroxy, mercapto, nitro, cyano, amino, acylamino, azido, guanidino,amidino, carboxyl, carboxamido, carboxamido alkyl, formyl, acyl,carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy,heterocycleoxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl,mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl,guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl orphosphonic group; wherein, the primary or secondary substitutents mayoptionally be bridged by covalent bonds to form one or more fused cyclicor heterocyclic systems with each other; wherein, the other substitutionat the alpha-carbon of Y may be substituted with hydrogen, alkyl,aminoalkyl, hydroxyalkyl or carboxyalkyl; wherein, the othersubstitution at the alpha-carbon of Z may be substituted with hydrogen,alkyl, aminoalkyl, hydroxyalkyl or carboxyalkyl; and whereinX_(aa1)—X_(aan) is a message sequence capable of inducing receptormediated signal transduction.
 46. The method of claim 45 wherein thepolypeptide mimics the activity of an endogenous polypeptide receptoragonist.
 47. The method of claim 45 wherein the polypeptide receptoragonist is GLP-1.
 48. The method of claim 45 further comprisingreplacing the message sequence of the polypeptide receptor agonist witha variant message sequence capable of inducing receptor mediated signaltransduction.
 49. An isolated polypeptide according to claims 1, 5, 9 or13, wherein the isolated polypeptide is selected from the following:Com- pound # Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 Xaa7 Xaa8 Xaa9 Y Z—NH₂ 1 H AE G T F T S D Bip(2-Et) Bip(2-Me) 2 H A D G T Phe(penta-Fluoro) T S DBip(2-Me) Bip(2-Me) 3 H A D G Nle Phe(penta-Fluoro) T S D Bip(2-Me)Bip(2-Me) 4 H A E G T Phe(penta-Fluoro) T S D Bip(2-Et) Bip(2-Me) 5 H AD G Nle Phe(penta-Fluoro) T S D Bip(2-Et) Bip(2-Me) 6 H A D G TPhe(penta-Fluoro) T S D Bip(2-Et) Bip(2-Me) 7 H ala D G NlePhe(penta-Fluoro) T S D Bip(2-Et) Bip(2-Me) 8 H ala D G Nle F T S DBip(2-Et) Bip(2-Me) 9 H A E G T F T S D Bip(2-Et,2′-Me) Bip(2-Me) 10 H AE G T F T S D Bip(2-Et,4-OMe) Bip(2-Me) 11 H A E G T F T S D Bip(2-Et)Bip(2,4-di—Me) 12 H A E G T F T S D Bip(2-Et) Bip(2,3-di—Me) 13 H A E GT Phe(penta-Fluoro) T H D Bip(2-Me) Bip(2-Me) 14 H Aib D G NlePhe(penta-Fluoro) T S D Bip(2-Et) Bip(2-Me) 15 H A E G NlePhe(penta-Fluoro) T S D Bip(2-Et) Bip(2-Me) 16 H A D G NlePhe(penta-Fluoro) T H D Bip(2-Et) Bip(2-Me) 17 H Aib D G NlePhe(penta-Fluoro) T S D Bip(2-Me) Bip(2-Me) 18 H A D G T L-α-Me—Phe T SD Bip(2-Me) Bip(2-Me) 19 H A E G Nle L-α-Me—Phe T S D Bip(2-Me)Bip(2-Me) 20 H A D G Nle L-α-Me—Phe T S D Bip(2-Me) Bip(2-Me) 21 H ala DG Nle L-α-Me—Phe T S D Bip(2-Me) Bip(2-Me) 22 H ala E G Nle L-α-Me—Phe TS D Bip(2-Me) Bip(2-Me) 23 H ala E G T L-α-Me—Phe T S D Bip(2-Me)Bip(2-Me) 24 H Aib D G T L-α-Me—Phe T S D Bip(2-Me) Bip(2-Me) 25 H Aib DG Nle L-α-Me—Phe T S D Bip(2-Me) Bip(2-Me) 26 H Aib E G Nle L-α-Me—Phe TS D Bip(2-Me) Bip(2-Me) 27 H A E G T F T S D Bip(2-Et,4,5- Bip(2-Me)di—OMe) 28 H A E G T L-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) 29 H A D G TL-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) 30 H A D G Nle L-α-Me—Phe T S DBip(2-Et) Bip(2-Me) 31 H ala D G T L-α-Me—Phe T S D Bip(2-Me) Bip(2-Me)32 H ala D G T L-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) 33 H ala D G NleL-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) 34 H Aib D G Nle L-α-Me—Phe T S DBip(2-Et) Bip(2-Me) 35 H Aib E G T L-α-Me—Phe T S D Bip(2-Et) Bip(2-Me)36 H Aib E G T L-α-Me—Phe T S D Bip(2-Me) Bip(2-Me) 37 H A D G NlePhe(penta-Fluoro) T S D Bip(2-Et,4-OMe) Bip(2-Me) 38 H A D G TPhe(penta-Fluoro) T S D Bip(2-Et,4-OMe) Bip(2-Me) 39 H Aib D G NlePhe(penta-Fluoro) T S D Bip(2-Et,4-OMe) Bip(2-Me) 40 H A D G TL-α-Me—Phe T S D Bip(2-Me) Bip 41 H A D G T L-α-Me—Phe T S D Bip(2-Et)Bip 42 H A E G T L-α-Me—Phe T S D Bip(2-Me) Bip(2-Me) 43 H A E G NleL-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) 44 H Aib E G Nle L-α-Me—Phe T S DBip(2-Et) Bip(2-Me) 45 H A D G T L-α-Me—Phe T S D Bip Bip(2-Me) 46 H A EG T F T S D Bip(2-Et,4-OMe) Bip(2-Me,4- OMe) 47 H A E G T F T S DBip(2-Et,4-OMe) Bip(2,3-di—Me) 48 H A E G T F T S D Bip(2-Et,4-OMe)Bip(2,4,5-tri—Me) 49 H A E G T F T S D Bip(2-Et,4-OMe) Bip(3,4-Methylenedioxy) 50 H A E G T F T S D Bip(2-Et,4-OMe) Bip(4-Me) 51 H A EG Nle Phe(penta-Fluoro) T S D Bip(2-Et,2′-Me) Bip(2-Me) 52 H A D G NlePhe(penta-Fluoro) T S D Bip(2-Et,2′-Me) Bip(2-Me) 53 H A D G TPhe(penta-Fluoro) T S D Bip(2-Et,2′-Me) Bip(2-Me) 54 H ala D G NlePhe(penta-Fluoro) T S D Bip(2-Et,2′-Me) Bip(2-Me) 55 H ala E G NlePhe(penta-Fluoro) T H D Bip(2-Et) Bip(2-Me) 56 H A E G T F T S DBip(2-Et,2′-Me) Bip 57 H L-α- E G T F T S D Bip(2-Et) Bip(2-Me) Me—Pro58 H L-α- E G T L-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) Me—Pro 59 H L-α- DG T L-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) Me—Pro 60 H A E G T L-α-Me—PheT S D Bip(2-Et,4-OMe) Bip(2-Me) 61 H A E G Nle L-α-Me—Phe T S DBip(2-Et,4-OMe) Bip(2-Me) 62 H A D G Nle L-α-Me—Phe T S DBip(2-Et,4-OMe) Bip(2-Me) 63 H ala E G Nle L-α-Me—Phe T S DBip(2-Et,4-OMe) Bip(2-Me) 64 H Aib D G T L-α-Me—Phe T S DBip(2-Et,4-OMe) Bip(2-Me) 65 H A E G T L-α-Me—Phe T S D Bip(2-Et)Bip(3,4- Methylenedioxy) 66 H A D G T Phe(2-Fluoro) T S D Bip(2-Me)Bip(2-Me) 67 H A D G Nle Phe(penta-Fluoro) T H D Bip(2-Me) Bip(2-Me) 68H A D G T Phe(penta-Fluoro) T S D Bip(2,4- Bip(2-Me) di—OMe) 69 H ala DG T L-α-Me—Phe T S D Bip(2-Et,4-OMe) Bip(2-Me) 70 H ala D G T L-α-Me—PheT S D Bip(2-Et,4-OMe) Bip(2-Me) 71 H A E G T L-α-Me—Phe T S D Bip(2-Et)Bip(4-SMe) 72 H A D G T L-α-Me—Phe T S D Bip(2-Et) Bip(3-Me) 73 H A D GT (L)-α-Me—Phe(2- T S D Bip(2-Et) Bip(2-Me) Fluoro) 74 H A E G T(L)-α-Me—Phe(2- T S D Bip(2-Et) Bip(2-Me) Fluoro) 75 H A D G Nle(L)-α-Me—Phe(2- T S D Bip(2-Et) Bip(2-Me) Fluoro) 76 H ala E G T(L)-α-Me—Phe(2- T S D Bip(2-Et) Bip(2-Me) Fluoro) 77 H ala D G T(L)-α-Me—Phe(2- T S D Bip(2-Et) Bip(2-Me) Fluoro) 78 H ala D G Nle(L)-α-Me—Phe(2- T S D Bip(2-Et) Bip(2-Me) Fluoro) 79 H Aib E G T(L)-α-Me—Phe(2- T S D Bip(2-Et) Bip(2-Me) Fluoro) 80 H Aib D G T(L)-α-Me—Phe(2- T S D Bip(2-Et) Bip(2-Me) Fluoro) 81 H Aib D G Nle(L)-α-Me—Phe(2- T S D Bip(2-Et) Bip(2-Me) Fluoro) 82 H A E G T(L)-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) (penta-Fluoro) 83 H A D G T(L)-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) (penta-Fluoro) 84 H ala E G T(L)-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) (penta-Fluoro) 85 H ala D G T(L)-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) (penta-Fluoro) 86 H Aib E G T(L)-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) (penta-Fluoro) 87 H Aib D G T(L)-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) (penta-Fluoro) 88 H A E G T(D)-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) (penta-Fluoro) 89 H A D G T(D)-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) (penta-Fluoro) 90 H ala E G T(D)-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) (penta-Fluoro) 91 H ala D G T(D)-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) (penta-Fluoro) 92 H Aib E G T(D)-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) (penta-Fluoro) 93 H Aib D G T(D)-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) (penta-Fluoro) 94 H ala D G Nle FT S D Bip(2-Et,4-OMe) Bip(2-Me) 95 H Aib D G Nle F T S D Bip(2-Et,4-OMe)Bip(2-Me) 96 H A E G T F T S D Bip(2,4-di—Et) Bip(2-Me) 97 H A D G TPhe(penta-Fluoro) T S D Bip(2,4-di—Et) Bip(2-Me) 98 H ala D G Nle F T SD Bip(2,4-di—Et) Bip(2-Me) 99 H ala E G T L-α-Me—Phe T S DBip(2-Et,4-OMe) Bip(2-Me) 100 H ala D G Nle L-α-Me—Phe T S DBip(2-Et,4-OMe) Bip(2-Me) 101 H Aib E G T L-α-Me—Phe T S DBip(2-Et,4-OMe) Bip(2-Me) 102 H Aib E G Nle L-α-Me—Phe T S DBip(2-Et,4-OMe) Bip(2-Me) 103 H Aib D G Nle L-α-Me—Phe T S DBip(2-Et,4-OMe) Bip(2-Me) 104 H A E G T L-α-Me—Phe T S D Bip(2,4-di—Et)Bip(2-Me) 105 H A D G T L-α-Me—Phe T S D Bip(2,4-di—Et) Bip(2-Me) 106 HA D G Nle L-α-Me—Phe T S D Bip(2,4-di—Et) Bip(2-Me) 107 H ala D G TL-α-Me—Phe T S D Bip(2,4-di—Et) Bip(2-Me) 108 H ala D G Nle L-α-Me—Phe TS D Bip(2,4-di—Et) Bip(2-Me) 109 H Aib D G T L-α-Me—Phe T S DBip(2,4-di—Et) Bip(2-Me) 110 H Aib D G Nle L-α-Me—Phe T S DBip(2,4-di—Et) Bip(2-Me) 111 H A D G T (L)-α-Ethyl-Phe T S D Bip(2-Et)Bip(2-Me) 112 H ala D G T (L)-α-Ethyl-Phe T S D Bip(2-Et) Bip(2-Me) 113H Aib D G T (L)-α-Ethyl-Phe T S D Bip(2-Et) Bip(2-Me) 114 H A E G T(L)-α-Me—Phe(2- T S D Bip(2-Et,4-OMe) Bip(2-Me) Fluoro) 115 H A D G T(L)-α-Me—Phe(2- T S D Bip(2-Et,4-OMe) Bip(2-Me) Fluoro) 116 H A D G Nle(L)-α-Me—Phe(2- T S D Bip(2-Et,4-OMe) Bip(2-Me) Fluoro) 117 H ala E G T(L)-α-Me—Phe(2- T S D Bip(2-Et,4-OMe) Bip(2-Me) Fluoro) 118 H ala D G T(L)-α-Me—Phe(2- T S D Bip(2-Et,4-OMe) Bip(2-Me) Fluoro) 119 H ala D GNle (L)-α-Me—Phe(2- T S D Bip(2-Et,4-OMe) Bip(2-Me) Fluoro) 120 H Aib EG T (L)-α-Me—Phe(2- T S D Bip(2-Et,4-OMe) Bip(2-Me) Fluoro) 121 H Aib DG T (L)-α-Me—Phe(2- T S D Bip(2-Et,4-OMe) Bip(2-Me) Fluoro) 122 H Aib DG Nle (L)-α-Me—Phe(2- T S D Bip(2-Et,4-OMe) Bip(2-Me) Fluoro) 123 H A EG T (L)-α-Me—Phe T S D Bip(2-Et,4-OMe) Bip(2-Me) (penta-Fluoro) 124 H AD G T (L)-α-Me—Phe T S D Bip(2-Et,4-OMe) Bip(2-Me) (penta-Fluoro) 125 Hala E G T (L)-α-Me—Phe T S D Bip(2-Et,4-OMe) Bip(2-Me) (penta-Fluoro)126 H ala D G T (L)-α-Me—Phe T S D Bip(2-Et,4-OMe) Bip(2-Me)(penta-Fluoro) 127 H Aib E G T (L)-α-Me—Phe T S D Bip(2-Et,4-OMe)Bip(2-Me) (penta-Fluoro) 128 H Aib D G T (L)-α-Me—Phe T S DBip(2-Et,4-OMe) Bip(2-Me) (penta-Fluoro) 129 H A D G Nle (D,L)-α-Me—PheT S D Bip(2-Et) Bip(2-Me) (penta-Fluoro) 130 H ala D G Nle(D,L)-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) (penta-Fluoro) 131 H Aib D GNle (D,L)-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) (penta-Fluoro) 132des—NH2—His Aib E G T (L)-(α-Me)Phe T S D Bip(2-Et) Bip(2-Me) 133 H A DG S L-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) 134 H A D G hSer L-α-Me—Phe T SD Bip(2-Et) Bip(2-Me) 135 H A D G Nva L-α-Me—Phe T S D Bip(2-Et)Bip(2-Me) 136 H A D G T L-α-Me—Phe S S D Bip(2-Et) Bip(2-Me) 137 H A D GT L-α-Me—Phe hSer S D Bip(2-Et) Bip(2-Me) 138 H A D G T L-α-Me—Phe T N DBip(2-Et) Bip(2-Me) 139 H A D G T L-α-Me—Phe T H D Bip(2-Et) Bip(2-Me)140 H A D G T L-α-Me—Phe T S Gla Bip(2-Et) Bip(2-Me) 141 H A D G TL-α-Me—Phe T S Adp Bip(2-Et) Bip(2-Me) 142 des—NH2—His A D G TL-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) 143 des—NH2—His Aib D G TL-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) 144 des—NH2—His ala D G TL-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) 145 H G D G Nle L-α-Me—Phe T S DBip(2-Et) Bip(2-Me) 146 H G E G Nle L-α-Me—Phe T S D Bip(2-Et) Bip(2-Me)147 H A E G T L-α-Me—Phe T S D Bip(2-Et) Bip(4-Et) 148 H A D G TL-α-Me—Phe T S D Bip(2-Et) Bip(4-Et) 149 H A E G T L-α-Me—Phe T S DBip(2-Et) Bip(2,4-di—Me) 150 H A D G T L-α-Me—Phe T S D Bip(2-Et)Bip(2,4-di—Me) 151 H A E G T L-α-Me—Phe T S D Bip(2-Et) Bip(2-Me,4- OMe)152 H A D G T L-α-Me—Phe T S D Bip(2-Et) Bip(2-Me,4- OMe) 153 H A E G TL-α-Me—Phe T S D Bip(2-Et) Bip(4-Me) 154 H A D G T L-α-Me—Phe T S DBip(2-Et) Bip(4-Me) 155 H Aib D G Nle L-α-Me—Phe T S D bip(2-Et)Bip(2-Me) 156 H ala D G Nle L-α-Me—Phe T S D Bip(2-Et)-NH-[2-(penta-Fluoro- phenyl)ethyl] 157 H A E G T (D,L)-Phe(2,6-di- T S DBip(2-Et) Bip(2-Me) Fluoro) 158 H A D G T L-Phe(2,6-di- T S D Bip(2-Et)Bip(2-Me) Fluoro) 159 H A E G Nle (D,L)-Phe(2,6-di- T S D Bip(2-Et)Bip(2-Me) Fluoro) 160 H A D G Nle (D,L)-Phe(2,6-di- T S D Bip(2-Et)Bip(2-Me) Fluoro) 161 H ala D G T L-Phe(2,6-di T S D Bip(2-Et) Bip(2-Me)Fluoro) 162 H ala E G Nle (D,L)-Phe(2,6-di- T S D Bip(2-Et) Bip(2-Me)Fluoro) 163 H ala D G Nle (D,L)-Phe(2,6-di T S D Bip(2-Et) Bip(2-Me)Fluoro) 164 H Aib E G T L-Phe(2,6-di- T S D Bip(2-Et) Bip(2-Me) Fluoro)165 H Aib D G T L-Phe(2,6-di- T S D Bip(2-Et) Bip(2-Me) Fluoro) 166 HAib E G Nle (D,L)-Phe(2,6-di- T S D Bip(2-Et) Bip(2-Me) Fluoro) 167 HAib D G Nle (D,L)-Phe(2,6-di- T S D Bip(2-Et) Bip(2-Me) Fluoro) 168 H AD G T (D,L)-Phe(2,6-di- T S D Bip(2-Et) Bip(2-Me) Fluoro) 169 H Aib E GT (D,L)-Phe(2,6-di- T S D Bip(2-Et) Bip(2-Me) Fluoro) 170 H Aib E G T(D)-α-Me—Phe T S D Bip(2-Et,4-OMe) Bip(2-Me) (penta-Fluoro) 171 H Aib DG T (D)-α-Me—Phe T S D Bip(2-Et,4-OMe) Bip(2-Me) (penta-Fluoro) 172 H AE G T L-α-Me—Phe T S D Bip(2-Ac) Bip(2-Me) 173 H A E G T L-α-Me—Phe T SD Bip(2,5- Bip(2-Me) di—OMe) 174 H A E G T L-α-Me—Phe T S DBip(2,5-di—Me) Bip(2-Me) 175 H A E G T L-α-Me—Phe T S D Bip(3,4-Bip(2-Me) di—OMe) 176 H A E G T L-α-Me—Phe T S D Bip(2,6-di—Cl)Bip(2-Me) 177 H Aib D G T L-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) 178 H(L)- E G Nle L-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) α- Me—Pro 179 H (L)- DG Nle L-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) α- Me—Pro 180 des—NH2—His(L)- E G T L-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) α- Me—Pro 181 H A D G(D,L F T S D Bip(2-Et) Bip(2-Me) )-α- Me—Nle 182 H A D G T L-α-Me—Phe TS D Bip(2-Et) (D,L)-α-Me—Bip 183 H ala D G T L-α-Me—Phe T S D Bip(2-Et)(D,L)-α-Me—Bip 184 H Aib D G T L-α-Me—Phe T S D Bip(2-Et) (D,L)-α-Me—Bip185 H A E G T L-Phe(2-Fluoro) T S D Bip(2-Et) Bip(2-Me) 186 H A D G TL-Phe(2-Fluoro) T S D Bip(2-Et) Bip(2-Me) 187 H A E G NleL-Phe(2-Fluoro) T S D Bip(2-Et) Bip(2-Me) 188 H A D G NleL-Phe(2-Fluoro) T S D Bip(2-Et) Bip(2-Me) 189 H ala D G TL-Phe(2-Fluoro) T S D Bip(2-Et) Bip(2-Me) 190 H ala E G NleL-Phe(2-Fluoro) T S D Bip(2-Et) Bip(2-Me) 191 H ala D G NleL-Phe(2-Fluoro) T S D Bip(2-Et) Bip(2-Me) 192 H Aib E G TL-Phe(2-Fluoro) T S D Bip(2-Et) Bip(2-Me) 193 H A D G T L-Phe(2,6-di- TS D Bip(2-Et,4-OMe) Bip(2-Me) Fluoro) 194 H ala D G Nle L-Phe(2,6-di- TS D Bip(2-Et,4-OMe) Bip(2-Me) Fluoro) 195 H Aib E G Nle L-Phe(2,6-di T SD Bip(2-Et,4-OMe) Bip(2-Me) Fluoro) 196 H Aib D G Nle L-Phe(2,6-di- T SD Bip(2-Et,4-OMe) Bip(2-Me) Fluoro) 197 H (L)- E G T L-α-Me—Phe T S DBip(2-Et,4-OMe) Bip(2-Me) α- Me—Pro 198 H (L)- D G T L-α-Me—Phe T S DBip(2-Et,4-OMe) Bip(2-Me) α- Me—Pro 199 H (L)- E G Nle L-α-Me—Phe T S DBip(2-Et,4-OMe) Bip(2-Me) α- Me—Pro 200 H (L)- D G Nle L-α-Me—Phe T S DBip(2-Et,4-OMe) Bip(2-Me) α- Me—Pro 201 des—NH2—His (L)- D G NleL-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) α- Me—Pro 202 H Aib D G NleD-Phe(2,6-di- T S D Bip(2-Et,4-OMe) Bip(2-Me) Fluoro) 203 des—NH2—His(L)- E G Nle L-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) α- Me—Pro 204 H A E GT (L)-α-Me—Phe T S D Bip(2-Et,4-OMe) Bip(2-Me) (2,6-di- Fluoro) 205 H AD G T (L)-α-Me—Phe T S D Bip(2-Et,4-OMe) Bip(2-Me) (2,6-di- Fluoro) 206H A D G T (L)-α-Me—Phe T S D Bip(2-Et,4-OMe) Bip(2-Me) (2,6-di- Fluoro)207 H ala E G T (L)-α-Me—Phe T S D Bip(2-Et,4-OMe) Bip(2-Me) (2,6-di-Fluoro) 208 H ala D G T (D,L)-α-Me—Phe T S D Bip(2-Et,4-OMe) Bip(2-Me)(2,6-di- Fluoro) 209 H Aib E G T (L)-α-Me—Phe T S D Bip(2-Et,4-OMe)Bip(2-Me) (2,6-di- Fluoro) 210 H Aib D G T (L)-α-Me—Phe T S DBip(2-Et,4-OMe) Bip(2-Me) (2,6-di- Fluoro) 211 H A E G T (L)-α-Me—Phe TS D Bip(2-Et) Bip(2-Me) (2,6-di- Fluoro) 212 H A D G T (L)-α-Me—Phe T SD Bip(2-Et) Bip(2-Me) (2,6-di- Fluoro) 213 H ala E G T (L)-α-Me—Phe T SD Bip(2-Et) Bip(2-Me) (2,6-di- Fluoro) 214 H ala D G T (D,L)-α-Me—Phe TS D Bip(2-Et) Bip(2-Me) (2,6-di- Fluoro) 215 H Aib E G T (L)-α-Me—Phe TS D Bip(2-Et) Bip(2-Me) (2,6-di- Fluoro) 216 H Aib D G T (D,L)-α-Me—PheT S D Bip(2-Et) Bip(2-Me) (2,6-di- Fluoro) 217 H Aib E G Nle(D)-α-Me—Phe T S D Bip(2-Et,4-OMe) Bip(2-Me) (2,6-di- Fluoro) 218 H AibD G Nle (D)-α-Me—Phe T S D Bip(2-Et,4-OMe) Bip(2-Me) (2,6-di- Fluoro)219 H A D G Nle (D)-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) (2,6-di- Fluoro)220 H ala E G T (D)-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) (2,6-di- Fluoro)221 H ala D G Nle (D,L)-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) (2,6-di-Fluoro) 222 H Aib E G T (D)-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) (2,6-di-Fluoro) 223 H Aib D G Nle (D)-α-Me—Phe T S D Bip(2-Et) Bip(2-Me)(2,6-di- Fluoro) 224 H A E G Nle (L)-α-Me—Phe(2- T S D Bip(2-Et,4-OMe)Bip(2-Me) Fluoro) 225 H ala E G Nle (L)-α-Me—Phe(2- T S DBip(2-Et,4-OMe) Bip(2-Me) Fluoro) 226 H Aib E G Nle (L)-α-Me—Phe(2- T SD Bip(2-Et,4-OMe) Bip(2-Me) Fluoro)


50. An isolated polypeptide according to claims 1, 5, 9 or 13, whereinthe isolated polypeptide is selected from the following: Com- pound #Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 Xaa7 Xaa8 Xaa9 Y Z—NH₂ 1 H A D G TPhe(penta-Fluoro) T S D Bip(2-Et) Bip(2-Me) 2 H A E G Nle L-α-Me—Phe T SD Bip(2-Me) Bip(2-Me) 3 H A D G Nle L-α-Me—Phe T S D Bip(2-Me) Bip(2-Me)4 H Aib D G T L-α-Me—Phe T S D Bip(2-Me) Bip(2-Me) 5 H Aib D G NleL-α-Me—Phe T S D Bip(2-Me) Bip(2-Me) 6 H A E G T L-α-Me—Phe T S DBip(2-Et) Bip(2-Me) 7 H A D G T L-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) 8 Hala D G Nle L-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) 9 H Aib D G NleL-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) 10 H Aib E G T L-α-Me—Phe T S DBip(2-Et) Bip(2-Me) 11 H A D G T Phe(penta-Fluoro) T S D Bip(2-Et,4-OMe)Bip(2-Me) 12 H A E G Nle L-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) 13 H Aib DG T L-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) 14 H A D G T Phe(penta-Fluoro)T S D Bip(2- Bip(2-Me) Ethyl,2′-Me) 15 H L-α-Me—Pro E G T L-α-Me—Phe T SD BIP(2-Et) Bip(2-Me) 16 H L-α-Me—Pro D G T L-α-Me—Phe T S D BIP(2-Et)Bip(2-Me) 17 H A D G Nva L-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) 18 H A D GT L-α-Me—Phe S S D Bip(2-Et) Bip(2-Me) 19 des—NH2—His A D G T L-α-Me—PheT S D Bip(2-Et) Bip(2-Me) 20 des—NH2—His Aib D G T L-α-Me—Phe T S DBip(2-Et) Bip(2-Me) 21 des—NH2—His ala D G T L-α-Me—Phe T S D Bip(2-Et)Bip(2-Me) 22 H G D G Nle L-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) 23 H A E GNle L-α-Me—Phe T S D BIP(2-Et,4- Bip(2-Me) Methoxy) 24 H A D G NleL-α-Me—Phe T S D BIP(2-Et,4- Bip(2-Me) Methoxy) 25 H ala E G NleL-α-Me—Phe T S D BIP(2-Et,4- Bip(2-Me) Methoxy) 26 H Aib D G TL-α-Me—Phe T S D BIP(2-Et,4-OMe) BIP(2-Me) 27 H A E G T L-α-Me—Phe T S DBip(2-Et) Bip(4-Et) 28 H A D G T L-α-Me—Phe T S D Bip(2-Et) Bip(4-Et) 29H A E G T L-α-Me—Phe T S D Bip(2-Et) Bip(2,4-di—Me) 30 H A D G TL-α-Me—Phe T S D Bip(2-Et) Bip(2,4-di—Me) 31 H A E G T L-α-Me—Phe T S DBip(2-Et) Bip(2-Me,4- OMe) 32 H A D G T L-α-Me—Phe T S D Bip(2-Et)Bip(2-Me,4- OMe) 33 H A E G T L-α-Me—Phe T S D Bip(2-Et) Bip(4-Me) 34 HA D G T L-α-Me—Phe T S D Bip(2-Et) Bip(4-Me) 35 H ala D G T L-α-Me—Phe TS D BIP(2-Et,4-OMe) BIP(2-Me) 36 H ala D G T L-α-Me—Phe T S DBIP(2-Et,4-OMe) BIP(2-Me) 37 H A E G T L-α-Me—Phe T S D BIP(2-Et)BIP(4-SMe) 38 H A D G T L-α-Me—Phe T S D BIP(2-Et) BIP(3-Me) 39 H A D GT (L)-α-Me—Phe T S D BIP(2-Et) BIP(2-Me) (penta-Fluoro) 40 H A E G T(L)-α-Me—Phe(2- T S D BIP(2-Et) BIP(2-Me) Fluoro) 41 H A D G Nle(L)-α-Me—Phe T S D BIP(2-Et) BIP(2-Me) (penta-Fluoro) 42 H ala E G T(L)-α-Me—Phe(2- T S D BIP(2-Et) BIP(2-Me) Fluoro) 43 H ala D G T(L)-α-Me—Phe(2- T S D BIP(2-Et) BIP(2-Me) Fluoro) 44 H ala D G Nle(L)-α-Me—Phe T S D BIP(2-Et) BIP(2-Me) (penta-Fluoro) 45 H Aib E G T(L)-α-Me—Phe(2- T S D BIP(2-Et) BIP(2-Me) Fluoro) 46 H Aib D G T(L)-α-Me—Phe(2- T S D BIP(2-Et) BIP(2-Me) Fluoro) 47 H Aib D G Nle(L)-α-Me—Phe(2- T S D BIP(2-Et) BIP(2-Me) Fluoro) 48 H A E G T(L)-α-Me—Phe T S D BIP(2-Et) BIP(2-Me) (penta-Fluoro) 49 H A D G T(L)-α-Me—Phe T S D BIP(2-Et) BIP(2-Me) (penta-Fluoro) 50 H ala E G T(L)-α-Me—Phe T S D BIP(2-Et) BIP(2-Me) (penta-Fluoro) 51 H ala D G T(L)-α-Me—Phe T S D BIP(2-Et) BIP(2-Me) (penta-Fluoro) 52 H ala D G Nle(D,L)-α-Me—Phe T S D BIP(2-Et) BIP(2-Me) (penta-Fluoro) 53 H Aib E G T(L)-α-Me—Phe T S D BIP(2-Et) BIP(2-Me) (penta-Fluoro) 54 H Aib D G T(L)-α-Me—Phe T S D BIP(2-Et) BIP(2-Me) (penta-Fluoro) 55 H Aib D G Nle(D,L)-α-Me—Phe T S D BIP(2-Et) BIP(2-Me) (penta-Fluoro) 56 H A D G T(D)-α-Me—Phe T S D BIP(2-Et) BIP(2-Me) (penta-Fluoro) 57 H Aib E G T(D)-α-Me—Phe T S D BIP(2-Et) BIP(2-Me) (penta-Fluoro) 58 H Aib D G T(D)-α-Me—Phe T S D BIP(2-Et) BIP(2-Me) (penta-Fluoro) 59 H ala D G Nle FT S D BIP(2-Et,4-OMe) BIP(2-Me) 60 H Aib D G Nle F T S D BIP(2-Et,4-OMe)BIP(2-Me) 61 H ala E G T L-α-Me—Phe T S D BIP(2-Et,4-OMe) BIP(2-Me) 62 Hala D G Nle L-α-Me—Phe T S D BIP(2-Et,4-OMe) BIP(2-Me) 63 H Aib E G TL-α-Me—Phe T S D BIP(2-Et,4-OMe) BIP(2-Me) 64 H Aib E G Nle L-α-Me—Phe TS D BIP(2-Et,4-OMe) BIP(2-Me) 65 H Aib D G Nle L-α-Me—Phe T S DBIP(2-Et,4-OMe) BIP(2-Me) 66 H A E G T L-α-Me—Phe T S D BIP(2,4-di—Et)BIP(2-Me) 67 H A D G T L-α-Me—Phe T S D BIP(2,4-di—Et) BIP(2-Me) 68 H AD G Nle L-α-Me—Phe T S D BIP(2,4-di—Et) BIP(2-Me) 69 H ala D G TL-α-Me—Phe T S D BIP(2,4-di—Et) BIP(2-Me) 70 H ala D G Nle L-α-Me—Phe TS D BIP(2,4-di—Et) BIP(2-Me) 71 H Aib D G T L-α-Me—Phe T S DBIP(2,4-di—Et) BIP(2-Me) 72 H Aib D G Nle L-α-Me—Phe T S DBIP(2,4-di—Et) BIP(2-Me) 73 H A D G T (L)-Phe(2,6-di- T S D Bip(2-Et)Bip(2-Me) Fluoro) 74 H ala D G Nle (D,L)-Phe(2,6-di- T S D Bip(2-Et)Bip(2-Me) Fluoro) 75 H Aib E G T (L)-Phe(2,6-di- T S D Bip(2-Et)Bip(2-Me) Fluoro) 76 H Aib D G T (L)-Phe(2,6-di- T S D Bip(2-Et)Bip(2-Me) Fluoro) 77 H Aib E G Nle (D,L)-Phe(2,6-di- T S D Bip(2-Et)Bip(2-Me) Fluoro) 78 H Aib D G Nle (D,L)-Phe(2,6-di- T S D Bip(2-Et)Bip(2-Me) Fluoro) 79 H A D G T (L)-α-Me—Phe(2- T S D Bip(2-Et,4-OMe)Bip(2-Me) Fluoro) 80 H ala D G T (L)-α-Me—Phe(2- T S D Bip(2-Et,4-OMe)Bip(2-Me) Fluoro) 81 H Aib D G T (L)-α-Me—Phe(2- T S D Bip(2-Et,4-OMe)Bip(2-Me) Fluoro) 82 H A E G T L-α-Me—Phe T S D Bip(3,4- Bip(2-Me)di—OMe) 83 H Aib E G T (D)-Phe(2,6-di- T S D Bip(2-Et) Bip(2-Me) Fluoro)84 H L-α-Me—Pro E G Nle L-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) 85 HL-α-Me—Pro D G Nle L-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) 86 H Aib D G TL-α-Me—Phe T S D Bip(2-Et) (D,L)-α-Me—Bip 87 H ala D G Nle Phe(2-Fluoro)T S D Bip(2-Et) Bip(2-Me) 88 H A D G T (L)-Phe(2,6-di- T S DBip(2-Et,4-OMe) Bip(2-Me) Fluoro) 89 H ala D G Nle (L)-Phe(2,6-di- T S DBip(2-Et,4-OMe) Bip(2-Me) Fluoro) 90 H Aib E G Nle (L)-Phe(2,6-di- T S DBip(2-Et,4-OMe) Bip(2-Me) Fluoro) 91 H Aib D G Nle (L)-Phe(2,6-di- T S DBip(2-Et,4-OMe) Bip(2-Me) Fluoro) 92 H L-α-Me—Pro E G T L-α-Me—Phe T S DBip(2-Et,4-OMe) Bip(2-Me) 93 H L-α-Me—Pro D G T L-α-Me—Phe T S DBip(2-Et,4-OMe) Bip(2-Me) 94 H L-α-Me—Pro E G Nle L-α-Me—Phe T S DBip(2-Et,4-OMe) Bip(2-Me) 95 H L-α-Me—Pro D G Nle L-α-Me—Phe T S DBip(2-Et,4-OMe) Bip(2-Me) 96 des—NH2—His L-α-Me—Pro D G Nle L-α-Me—Phe TS D Bip(2-Et) Bip(2-Me) 97 des—NH2—His L-α-Me—Pro E G Nle L-α-Me—Phe T SD Bip(2-Et) Bip(2-Me) 98 H ala E G Nle (L)-α-Me—Phe(2- T S DBip(2-Et,4-OMe) Bip(2-Me) Fluoro) 99 H Aib E G Nle (L)-α-Me—Phe(2- T S DBip(2-Et,4-OMe) Bip(2-Me) Fluoro) 100 H A E G T (L)-α-Me—Phe(2,6- T S DBip(2-Et,4-OMe) Bip(2-Me) di-Fluoro) 101 H A D G T (L)-α-Me—Phe(2,6- T SD Bip(2-Et,4-OMe) Bip(2-Me) di-Fluoro) 102 H ala E G T (L)-α-Me—Phe(2,6-T S D Bip(2-Et,4-OMe) Bip(2-Me) di-Fluoro) 103 H ala D G T(D,L)-α-Me—Phe T S D Bip(2-Et,4-OMe) Bip(2-Me) (2,6-di-Fluoro) 104 H AibE G T (L)-α-Me—Phe(2,6- T S D Bip(2-Et,4-OMe) Bip(2-Me) di-Fluoro) 105 HAib D G T (L)-α-Me—Phe(2,6- T S D Bip(2-Et,4-OMe) Bip(2-Me) di-Fluoro)106 H A E G T (L)-α-Me—Phe(2,6- T S D Bip(2-Et) Bip(2-Me) di-Fluoro) 107H A D G T (L)-α-Me—Phe(2,6- T S D Bip(2-Et) Bip(2-Me) di-Fluoro) 108 Hala E G T (L)-α-Me—Phe(2,6- T S D Bip(2-Et) Bip(2-Me) di-Fluoro) 109 Hala D G T (D,L)-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) (2,6-di-Fluoro) 110 HAib E G T (L)-α-Me—Phe(2,6- T S D Bip(2-Et) Bip(2-Me) di-Fluoro) 111 HAib D G T (D,L)-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) (2,6-di-Fluoro) 112 HAib E G Nle (D)-α-Me—Phe(2,6- T S D Bip(2-Et,4-OMe) Bip(2-Me) di-Fluoro)113 H Aib D G Nle (D)-α-Me—Phe(2,6- T S D Bip(2-Et,4-OMe) Bip(2-Me)di-Fluoro) 114 H A D G Nle (D)-α-Me—Phe(2,6- T S D Bip(2-Et) Bip(2-Me)di-Fluoro) 115 H ala E G T (D)-α-Me—Phe(2,6- T S D Bip(2-Et) Bip(2-Me)di-Fluoro) 116 H ala D G Nle (D,L)-α-Me—Phe T S D Bip(2-Et) Bip(2-Me)(2,6-di-Fluoro) 117 H Aib E G T (D)-α-Me—Phe(2,6- T S D Bip(2-Et)Bip(2-Me) di-Fluoro) 118 H Aib D G Nle (D)-α-Me—Phe(2,6- T S D Bip(2-Et)Bip(2-Me) di-Fluoro) 119 des—NH2—His Aib E G T L-α-Me—Phe T S DBip(2-Et) Bip(2-Me) 122 H Aib D G Nle (L)-α-Me—Phe(2- T S DBip(2-Et,4-OMe) Bip(2-Me) Fluoro) 123 H Aib E G T (L)-α-Me—Phe(2- T S DBip(2-Et,4-OMe) Bip(2-Me) Fluoro) 124 H ala D G Nle (L)-α-Me—Phe(2- T SD Bip(2-Et,4-OMe) Bip(2-Me) Fluoro) 125 H ala E G T (L)-α-Me—Phe(2- T SD Bip(2-Et,4-OMe) Bip(2-Me) Fluoro) 126 H A D G Nle (L)-α-Me—Phe(2- T SD Bip(2-Et,4-OMe) Bip(2-Me) Fluoro) 127 H A E G T (L)-α-Me—Phe(2- T S DBip(2-Et,4-OMe) Bip(2-Me) Fluoro) 128 H Aib D G T (L)-α-Me—Phe T S DBip(2-Et,4-OMe) Bip(2-Me) (penta-Fluoro) 129 H Aib E G T (L)-α-Me—Phe TS D Bip(2-Et,4-OMe) Bip(2-Me) (penta-Fluoro) 130 H ala D G T(L)-α-Me—Phe T S D Bip(2-Et,4-OMe) Bip(2-Me) (penta-Fluoro) 131 H ala EG T (L)-α-Me—Phe T S D Bip(2-Et,4-OMe) Bip(2-Me) (penta-Fluoro) 132 H AD G T (L)-α-Me—Phe T S D Bip(2-Et,4-OMe) Bip(2-Me) (penta-Fluoro) 133 HA E G T (L)-α-Me—Phe T S D Bip(2-Et,4-OMe) Bip(2-Me) (penta-Fluoro)


51. An isolated polypeptide according to claims 1, 5, 9 or 13, whereinthe isolated polypeptide is selected from the following: Compound # Xaa1Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 Xaa7 Xaa8 Xaa9 Y Z—NH₂ 1 H ala D G NleL-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) 2 H L-α- E G T L-α-Me—Phe T S DBip(2-Et) Bip(2-Me) Me—Pro 3 H L-α- D G T L-α-Me—Phe T S D Bip(2-Et)Bip(2-Me) Me—Pro 4 H Aib D G T L-α-Me—Phe T S D BIP(2-Et,4- BIP(2-Me)OMe) 5 H ala D G T L-α-Me—Phe T S D BIP(2-Et,4- BIP(2-Me) OMe) 6 H A D GT L-α-Me—Phe T S D BIP(2-Et) BIP(3-Me) 7 H A D G T (L)-α-Me—Phe T S DBIP(2-Et) BIP(2-Me) (penta- Fluoro) 8 H A E G T (L)-α-Me—Phe T S DBIP(2-Et) BIP(2-Me) (2-Fluoro) 9 H A D G Nle (L)-α-Me—Phe T S DBIP(2-Et) BIP(2-Me) (penta- Fluoro) 10 H ala E G T (L)-α-Me—Phe T S DBIP(2-Et) BIP(2-Me) (2-Fluoro) 11 H ala D G T (L)-α-Me—Phe T S DBIP(2-Et) BIP(2-Me) (2-Fluoro) 12 H ala D G Nle (L)-α-Me—Phe T S DBIP(2-Et) BIP(2-Me) (penta- Fluoro) 13 H Aib E G T (L)-α-Me—Phe T S DBIP(2-Et) BIP(2-Me) (2-Fluoro) 14 H Aib D G T (L)-α-Me—Phe T S DBIP(2-Et) BIP(2-Me) (2-Fluoro) 15 H Aib D G Nle (L)-α-Me—Phe T S DBIP(2-Et) BIP(2-Me) (2-Fluoro) 16 H A E G T (L)-α-Me—Phe T S D BIP(2-Et)BIP(2-Me) (penta- Fluoro) 17 H A D G T (L)-α-Me—Phe T S D BIP(2-Et)BIP(2-Me) (penta- Fluoro) 18 H ala E G T (L)-α-Me—Phe T S D BIP(2-Et)BIP(2-Me) (penta- Fluoro) 19 H ala D G T (L)-α-Me—Phe T S D BIP(2-Et)BIP(2-Me) (penta- Fluoro) 20 H ala D G Nle (D,L)-α-Me—Phe T S DBIP(2-Et) BIP(2-Me) (penta- Fluoro) 21 H Aib E G T (L)-α-Me—Phe T S DBIP(2-Et) BIP(2-Me) (penta- Fluoro) 22 H Aib D G T (L)-α-Me—Phe T S DBIP(2-Et) BIP(2-Me) (penta- Fluoro) 23 H Aib D G Nle (D,L)-α-Me—Phe T SD BIP(2-Et) BIP(2-Me) (penta- Fluoro) 24 H Aib D G Nle F T S DBIP(2-Et,4- BIP(2-Me) OMe) 25 H ala E G T L-α-Me—Phe T S D BIP(2-Et,4-BIP(2-Me) OMe) 26 H ala D G Nle L-α-Me—Phe T S D BIP(2-Et,4- BIP(2-Me)OMe) 27 H Aib E G T L-α-Me—Phe T S D BIP(2-Et,4- BIP(2-Me) OMe) 28 H AibE G Nle L-α-Me—Phe T S D BIP(2-Et,4- BIP(2-Me) OMe) 29 H Aib D G NleL-α-Me—Phe T S D BIP(2-Et,4- BIP(2-Me) OMe) 30 H A D G T L-α-Me—Phe T SD BIP(2,4-di—Et) BIP(2-Me) 31 H A D G Nle L-α-Me—Phe T S DBIP(2,4-di—Et) BIP(2-Me) 32 H ala D G T L-α-Me—Phe T S D BIP(2,4-di—Et)BIP(2-Me) 33 H Aib D G T L-α-Me—Phe T S D BIP(2,4-di—Et) BIP(2-Me) 34 HAib D G Nle L-α-Me—Phe T S D BIP(2,4-di—Et) BIP(2-Me) 35 H Aib D G Nle(D,L)-Phe(2,6- T S D Bip(2-Et) Bip(2-Me) di-Fluoro) 36 H A E G T(L)-α-Me—Phe T S D Bip(2-Et,4- Bip(2-Me) (2-Fluoro) OMe) 37 H A D G T(L)-α-Me—Phe T S D Bip(2-Et,4- Bip(2-Me) (2-Fluoro) OMe) 38 H A D G Nle(L)-α-Me—Phe T S D Bip(2-Et,4- Bip(2-Me) (2-Fluoro) OMe) 39 H ala E G T(L)-α-Me—Phe T S D Bip(2-Et,4- Bip(2-Me) (2-Fluoro) OMe) 40 H ala D G T(L)-α-Me—Phe T S D Bip(2-Et,4- Bip(2-Me) (2-Fluoro) OMe) 41 H ala D GNle (L)-α-Me—Phe T S D Bip(2-Et,4- Bip(2-Me) (2-Fluoro) OMe) 42 H Aib EG T (L)-α-Me—Phe T S D Bip(2-Et,4- Bip(2-Me) (2-Fluoro) OMe) 43 H Aib DG T (L)-α-Me—Phe T S D Bip(2-Et,4- Bip(2-Me) (2-Fluoro) OMe) 44 H Aib DG Nle (L)-α-Me—Phe T S D Bip(2-Et,4- Bip(2-Me) (2-Fluoro) OMe) 45 H AibE G T (L)-α-Me—Phe T S D Bip(2-Et,4- Bip(2-Me) (penta- OMe) Fluoro) 46 HAib D G T (L)-α-Me—Phe T S D Bip(2-Et,4- Bip(2-Me) (penta- OMe) Fluoro)47 H A D G T (L)-Phe(2,6- T S D Bip(2-Et,4- Bip(2-Me) di-Fluoro) OMe) 48H L-α- E G T L-α-Me—Phe T S D Bip(2-Et,4- Bip(2-Me) Me—Pro OMe) 49 HL-α- E G Nle L-α-Me—Phe T S D Bip(2-Et,4- Bip(2-Me) Me—Pro OMe) 50 HL-α- D G Nle L-α-Me—Phe T S D Bip(2-Et,4- Bip(2-Me) Me—Pro OMe) 51 H A EG T (L)-α-Me—Phe T S D Bip(2-Et,4- Bip(2-Me) (2,6-di- OMe) Fluoro) 52 HAib E G T (L)-α-Me—Phe T S D Bip(2-Et,4- Bip(2-Me) (2,6-di- OMe) Fluoro)53 H Aib D G T (L)-α-Me—Phe T S D Bip(2-Et,4- Bip(2-Me) (2,6-di- OMe)Fluoro) 54 H A E G T (L)-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) (2,6-di-Fluoro) 55 H A D G T (L)-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) (2,6-di-Fluoro) 56 H Aib E G T (L)-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) (2,6-di-Fluoro) 57 H Aib D G T (D,L)-α-Me—Phe T S D Bip(2-Et) Bip(2-Me) (2,6-di-Fluoro) 58 H Aib E G Nle (D)-α-Me—Phe T S D Bip(2-Et,4- Bip(2-Me)(2,6-di- OMe) Fluoro) 59 H Aib D G Nle (D)-α-Me—Phe T S D Bip(2-Et,4-Bip(2-Me) (2,6-di- OMe) Fluoro) 60 H ala D G Nle (D,L)-α-Me—Phe T S DBip(2-Et) Bip(2-Me) (2,6-di- Fluoro) 61 H Aib D G Nle (D)-α-Me—Phe T S DBip(2-Et) Bip(2-Me) (2,6-di- Fluoro)


52. A pharmaceutical composition comprising a compound as defined inclaims 1, 12, 24 or 35 and a pharmaceutically acceptable carriertherefor.
 53. A pharmaceutical combination comprising a compound asdefined in claims 1, 12, 24 or 35 and at least one therapeutic agentselected from the group consisting of an antidiabetic agent, ananti-obesity agent, a anti-hypertensive agent, an anti-atheroscleroticagent and a lipid-lowering agent.
 54. The combination as defined inclaim 53 wherein the antidiabetic agent is at least one agent selectedfrom the group consisting of a biguanide, a sulfonyl urea, a glucosidaseinhibitor, a PPAR γ agonist, a PPAR α/γ dual agonist, an aP2 inhibitor,a DP4 inhibitor, an insulin sensitizer, a glucagon-like peptide-1(GLP-1), insulin and a meglitinide.
 55. The combination as defined inclaim 54 wherein the antidiabetic agent is at least one agent selectedfrom the group consisting of metformin, glyburide, glimepiride,glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol,pioglitazone, troglitazone, rosiglitazone, insulin, Gl-262570,isaglitazone, JTT-501, NN-2344, L895645, YM-440, R-119702, AJ9677,repaglinide, nateglinide, KAD1129, AR-HO39242, GW-409544, KRP297,AC2993, LY315902, and NVP-DPP-728A.
 56. The combination as defined inclaim 54 wherein the anti-obesity agent is at least one agent selectedfrom the group consisting of a beta 3 adrenergic agonist, a lipaseinhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroidreceptor beta compound, and an anorectic agent.
 57. The combination asdefined in claim 56 wherein the anti-obesity agent is at least one agentselected from the group consisting of orlistat, ATL-962, AJ9677,L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine,phentermine, phenylpropanolamine and mazindol.
 58. The combination asdefined in claim 54 wherein the lipid lowering agent is at least oneagent selected from the group consisting of an MTP inhibitor,cholesterol ester transfer protein, an HMG CoA reductase inhibitor, asqualene synthetase inhibitor, a fibric acid derivative, an upregulatorof LDL receptor activity, a lipoxygenase inhibitor, or an ACATinhibitor.
 59. The combination as defined in claim 58 wherein the lipidlowering agent is at least one agent selected from the group consistingof pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin,fluvastatin, nisvastatin, visastatin, fenofibrate, gemfibrozil,clofibrate, avasimibe, TS-962, MD-700, CP-529414, and/or LY295427.
 60. Amethod for treating or delaying the progression or onset of diabetes,diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, woundhealing, insulin resistance, hyperglycemia, hyperinsulinemia, SyndromeX, diabetic complications, elevated blood levels of free fatty acids orglycerol, hyperlipidemia, obesity, hypertriglyceridemia, atherosclerosisor hypertension, which comprises administering to a mammalian species inneed of treatment a therapeutically effective amount of a compound asdefined in claims 1, 12, 24 or
 35. 61. A method according to claim 60further comprising administering, concurrently or sequentially, atherapeutically effective amount of at least one additional therapeuticagent selected from the group consisting of an antidiabetic agent, ananti-obesity agent, a anti-hypertensive agent, an anti-atheroscleroticagent and a lipid-lowering agent.
 62. An isolated polypeptide accordingto claim 1 wherein the isolated polypeptide is selected from thefollowing: Compound # A Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 Xaa7 Xaa8 Xaa9 YZ-NH2 1 Y H Aib E G T (L)-α- T S D Bip(2- Bip(2- Me-Phe Et, 4- Me)-(2-Fluoro) OMe) NH2 2 Bip H Aib E G T (L)-α- T S D Bip(2- Bip(2- Me-PheEt, 4- Me)- (2- OMe) NH2 Fluoro) 3 CH₃CO H Aib E G T (L)-α- T S D Bip(2-Bip(2- Me-Phe Et, 4- Me)- (2-Fluoro) OMe) NH2 4 CH₃CH₂CO H Aib E G T(L)-α- T S D Bip(2- Bip(2- Me-Phe Et, 4- Me)- (2-Fluoro) OMe) NH2 5Des-NH₂-Tyr H Aib E G T (L)-α- T S D Bip(2- Bip(2- Me-Phe Et, 4- Me)-(2-Fluoro) OMe) NH2 6 CH₃OCO H Aib E G T (L)-α- T S D Bip(2- Bip(2-Me-Phe Et, 4- Me)- (2-Fluoro) OMe) NH2 7 CH₃NHCO H Aib E G T (L)-α- T SD Bip(2- Bip(2- Me-Phe Et, 4- Me)- (2-Fluoro) OMe) NH2 8 CH₃SO₂ H Aib EG T (L)-α- T S D Bip(2- Bip(2- Me-Phe Et, 4- Me)- (2-Fluoro) OMe) NH2 9(L)-OH—CH H Aib E G T (L)-α- T S D Bip(2- Bip(2- (CH₃)CO Me-Phe Et, 4-Me)- (2-Fluoro) OMe) NH2 10  HO—CH₂—CO— H Aib E G T (L)-α- T S D Bip(2-Bip(2- Me-Phe Et, 4- Me)- (2-Fluoro) OMe) NH2